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  • 151.
    Engling, Pit
    et al.
    Department of Molecular Infection Biology, Helmholtz Center for Infection Research, Braunschweig, Germany.
    Héchard, Tifaine
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Edgren, Tomas
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Francis, Matthew
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Dersch, Petra
    Department of Molecular Infection Biology, Helmholtz Center for Infection Research, Braunschweig, Germany; Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany.
    Wang, Helen
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Calcium-responsive plasmid copy number regulation is dependent on discrete YopD domains in Yersinia pseudotuberculosis2023Inngår i: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 126, artikkel-id 102683Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Yersinia pathogenicity depends mainly on a Type III Secretion System (T3SS) responsible for translocating effector proteins into the eukaryotic target cell cytosol. The T3SS is encoded on a 70 kb, low copy number virulence plasmid, pYV. A key T3SS regulator, YopD, is a multifunctional protein and consists of discrete modular domains that are essential for pore formation and translocation of Yop effectors. In Y. pseudotuberculosis, the temperature-dependent plasmid copy number increase that is essential for elevated T3SS gene dosage and virulence is also affected by YopD. Here, we found that the presence of intracellular YopD results in increased levels of the CopA-RNA and CopB, two inhibitors of plasmid replication. Secretion of YopD leads to decreased expression of copA and copB, resulting in increased plasmid copy number. Moreover, using a systematic mutagenesis of YopD mutants, we demonstrated that the same discrete modular domains important for YopD translocation are also necessary for both the regulation of plasmid copy number as well as copA and copB expression. Hence, Yersinia has evolved a mechanism coupling active secretion of a plasmid-encoded component of the T3SS, YopD, to the regulation of plasmid replication. Our work provides evidence for the cross-talk between plasmid-encoded functions with the IncFII replicon.

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  • 152.
    Engström, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Chlamydiae are important human bacterial pathogens with an intracellular life cycle that consists of two distinct bacterial forms, an infectious form (EB) that infects the eukaryotic host cell, and a non-infectious form (RB) that allows intracellular proliferation. To be successful, chlamydiae need to alternate between EB and RB to generate infectious EB’s which are competent to infect new host cells.

    Chemical genetics is an attractive approach to study bacterial pathogenesis; in principal this approach relies on an inhibitory compound that specifically inhibits a protein of interest. An obstacle in using this approach is target identification, however whole genome sequencing (WGS) of spontaneous mutants resistant to novel inhibitory compounds has significantly extended the utility of chemical genetic approaches by allowing the identification of their target proteins and/or biological pathways.

    In this thesis, a chemical genetics approach is used, I have found that heme and glucose metabolism of C. trachomatis is specifically important for the transition from the RB form to the infectious EB form. Heme and glucose metabolism are both coupled to energy metabolism, which suggests a common link between the RB-to-EB transitions. In connection with the above findings I have developed strategies that enable the isolation of isogenic C. trachomatis mutant strains. These strategies are based on WGS of spontaneous mutant populations and subsequent genotyping of clonal strains isolated from these mutant populations. Experiments with the mutant strains suggest that the uptake of glucose-6-phosphate (G-6-P) regulates the RB-to-EB transition, representing one of the first examples where genetics has been used to study C. trachomatis pathogenesis. Additional experiments with the mutant strains indicate that G-6-P promotes bacterial growth during metabolic stress.

    In concert with other findings presented in this thesis, I have fine-tuned methods that could be employed to reveal how novel inhibitory chemical compounds affect chlamydiae. In a broader context, I suggest that C. trachomatis could be used as a model organism to understand how new inhibitory drugs affect other bacterial pathogens.

    In addition, I observed that C. pneumoniae infections resulted in generalized bone loss in mice and that these mice display a cytokine profile similar to infected bone cells in vitro. Thus, this study indicates that C. pneumoniae potentially can infect bone cells in vivo, resulting in bone loss, alternatively, the inflammatory responses seen in vivo could be the causative factor of the bone loss observed.

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  • 153.
    Engström, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Bergström, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Alfaro, Astrid C.
    Krishnan, K. Syam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bahnan, Wael
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication2015Inngår i: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 305, nr 3, s. 378-382Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chlamydia trachomatis replication takes place inside of a host cell, exclusively within a vacuole known as the inclusion. During an infection, the inclusion expands to accommodate the increasing numbers of C. trachomatis. However, whether inclusion expansion requires bacterial replication and/or de novo protein synthesis has not been previously investigated in detail. Therefore, using a chemical biology approach, we herein investigated C. trachomatis inclusion expansion under varying conditions in vitro. Under normal cell culture conditions, inclusion expansion correlated with C trachomatis replication. When bacterial replication was inhibited using KSK120: an inhibitor that targets C. trachomatis glucose metabolism, inclusions expanded even in the absence of bacterial replication. In contrast, when bacterial protein synthesis was inhibited using chloramphenicol, expansion of inclusions was blocked. Together, these data suggest that de novo protein synthesis is necessary, whereas bacterial replication is dispensable for C trachomatis inclusion expansion. (C) 2015 The Authors. Published by Elsevier GmbH.

  • 154.
    Engström, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ngyuen, Bidong D.
    Chorell, Erik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bastidas, Robert J.
    Welch, Matthew D.
    Hultgren, Scott J.
    Wolf-Watz, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael H.
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis2015Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 6, nr 1, artikkel-id e02304-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.

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  • 155.
    Engström, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Nguyen, Bidong D.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Ingela
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Bastidas, Robert J.
    Gylfe, Åsa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Elofsson, Mikael
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fields, Kenneth A.
    Valdivia, Raphael H.
    Wolf-Watz, Hans
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity2013Inngår i: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 195, nr 18, s. 4221-4230Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Salicylidene acylhydrazides (SAHs) inhibit the type III secretion system (T3S) of Yersinia and other Gram-negative bacteria. In addition, SAHs restrict the growth and development of Chlamydia species. However, since the inhibition of Chlamydia growth by SAH is suppressed by the addition of excess iron and since SAHs have an iron-chelating capacity, their role as specific T3S inhibitors is unclear. We investigated here whether SAHs exhibit a function on C. trachomatis that goes beyond iron chelation. We found that the iron-saturated SAH INP0341 (IS-INP0341) specifically affects C. trachomatis infectivity with reduced generation of infectious elementary body (EB) progeny. Selection and isolation of spontaneous SAH-resistant mutant strains revealed that mutations in hemG suppressed the reduced infectivity caused by IS-INP0341 treatment. Structural modeling of C. trachomatis HemG predicts that the acquired mutations are located in the active site of the enzyme, suggesting that IS-INP0341 inhibits this domain of HemG and that protoporphyrinogen oxidase (HemG) and heme metabolism are important for C. trachomatis infectivity.

  • 156.
    Enquist, Per-Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gylfe, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hägglund, Ulrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Lindström, Pia
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Norberg-Scherman, Henrik
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Sundin, Charlotta
    Creative Antibiotics, Tvistevägen 48, SE90719 Umeå, Sweden.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens2012Inngår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1464-3405, Vol. 22, nr 10, s. 3550-3553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl-)methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell-based infection models.

  • 157.
    Eriksson, Jonas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Grundström, Christin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sauer-Eriksson, A Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Small Molecule Screening for Inhibitors of the YopH Phosphatase of Yersinia pseudotuberculosis2012Inngår i: Advances in Yersinia Research, New York: Springer, 2012, Vol. 954, s. 357-363Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Bacterial virulence systems are attractive targets for development of new antibacterial agents. Yersinia spp. utilize the type III secretion (T3S) system to secrete and translocate Yersinia outer proteins (Yop effectors) into the cytosol of the target cell and thereby overcome host defenses to successfully establish an infection. Thus, the Yop effectors constitute attractive targets for drug development. In the present study we apply small molecule screening to identify inhibitors of one of the secreted proteins YopH, a tyrosine phosphatase required for virulence. Characterization of seven inhibitors indicated that both competitive and noncompetitive inhibitors were identified with IC50 values of 6–20 μM.

  • 158.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity2019Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 10, artikkel-id 3493Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hydrogen peroxide (H2O2) has a major function in host-microbial interactions. Although most studies have focused on the endogenous H2O2 produced by immune cells to kill microbes, bacteria can also produce H2O2. How microbial H2O2 influences the dynamics of host-microbial interactions is unclear. Here we show that H2O2 released by Streptococcus pneumoniae inhibits inflammasomes, key components of the innate immune system, contributing to the pathogen colonization of the host. We also show that the oral commensal H2O2-producing bacteria Streptococcus oralis can block inflammasome activation. This study uncovers an unexpected role of H2O2 in immune suppression and demonstrates how, through this mechanism, bacteria might restrain the immune system to co-exist with the host.

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    fulltext
  • 159.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Infection Oncology Unit, Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, UKSH, Schwanenweg 20, Kiel, Germany.
    Gekara, Nelson O.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Hermann-Herder-Str. 11, Freiburg, Germany.
    Protocol for isolation of microbiota-derived membrane vesicles from mouse blood and colon2023Inngår i: STAR Protocols, E-ISSN 2666-1667, Vol. 4, nr 1, artikkel-id 102046Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bacterial membrane vesicles have emerged as gadgets allowing remote communication between the microbiota and distal host organs. Here we describe a protocol for enriching vesicles from serum and colon that could widely be adapted for other tissues. We detail pre-clearing of serum or colon fluids using 0.2-μm syringe filters and their concentration by centrifugal filter devices. We also describe vesicle isolation with qEV size exclusion columns and finally the concentration of isolated vesicle fractions for downstream analyses. For complete details on the use and execution of this protocol, please refer to Erttmann et al. (2022).1

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    fulltext
  • 160.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Härtlova, Anetta
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sloniecka, Marta
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Raffi, Faizal A. M.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Hosseinzadeh, Ava
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Edgren, Tomas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Rofougaran, Reza
    Resch, Ulrike
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Ek, Torben
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity2016Inngår i: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 45, nr 1, s. 106-118Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome- dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1 beta (IL-1 beta) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.

  • 161.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Swacha, Patrycja
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Aung, Kyaw Min
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Brindefalk, Björn
    CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
    Jiang, Hui
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Härtlova, Anetta
    Institute of Biomedicine, Department of Microbiology and Immunology, Sahlgrenska Academy/Faculty of Science, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
    Uhlin, Bernt Eric
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis2022Inngår i: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 55, nr 5, s. 847-861Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The microbiota are vital for immune homeostasis and provide a competitive barrier to bacterial and fungal pathogens. Here, we investigated how gut commensals modulate systemic immunity and response to viral infection. Antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming. The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions. Instead, membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells. DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner. In summary, this study establishes an important role for the microbiota in peripheral cGAS-STING activation, which promotes host resistance to systemic viral infections. Moreover, it uncovers an underappreciated risk of antibiotic use during viral infections.

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  • 162.
    Escobar-Salom, María
    et al.
    Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain; Centro de Investigación Biomédica en Red, Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
    Barceló, Isabel María
    Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain; Centro de Investigación Biomédica en Red, Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
    Jordana-Lluch, Elena
    Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.
    Torrens, Gabriel
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain; Centro de Investigación Biomédica en Red, Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
    Oliver, Antonio
    Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain; Centro de Investigación Biomédica en Red, Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
    Juan, Carlos
    Research Unit and Microbiology Department, University Hospital Son Espases-Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain; Centro de Investigación Biomédica en Red, Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
    Bacterial virulence regulation through soluble peptidoglycan fragments sensing and response: knowledge gaps and therapeutic potential2023Inngår i: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 47, nr 2Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Given the growing clinical-epidemiological threat posed by the phenomenon of antibiotic resistance, new therapeutic options are urgently needed, especially against top nosocomial pathogens such as those within the ESKAPE group. In this scenario, research is pushed to explore therapeutic alternatives and, among these, those oriented toward reducing bacterial pathogenic power could pose encouraging options. However, the first step in developing these antivirulence weapons is to find weak points in the bacterial biology to be attacked with the goal of dampening pathogenesis. In this regard, during the last decades some studies have directly/indirectly suggested that certain soluble peptidoglycan-derived fragments display virulence-regulatory capacities, likely through similar mechanisms to those followed to regulate the production of several β-lactamases: binding to specific transcriptional regulators and/or sensing/activation of two-component systems. These data suggest the existence of intra- and also intercellular peptidoglycan-derived signaling capable of impacting bacterial behavior, and hence likely exploitable from the therapeutic perspective. Using the well-known phenomenon of peptidoglycan metabolism-linked β-lactamase regulation as a starting point, we gather and integrate the studies connecting soluble peptidoglycan sensing with fitness/virulence regulation in Gram-negatives, dissecting the gaps in current knowledge that need filling to enable potential therapeutic strategy development, a topic which is also finally discussed.

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  • 163.
    Espaillat, Akbar
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Chr. Hansen A/S, Microbial Physiology, R & amp;D, Hoersholm, Denmark.
    Alvarez, Laura
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Torrens, Gabriel
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    ter Beek, Josy
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Miguel-Ruano, Vega
    Department of Crystallography and Structural Biology, Institute of Physical Chemistry “Blas Cabrera”, CSIC, Madrid, Spain.
    Irazoki, Oihane
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gago, Federico
    Department of Biomedical Sciences & amp; IQM-CSIC Associate Unit, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
    Hermoso, Juan A.
    Department of Crystallography and Structural Biology, Institute of Physical Chemistry “Blas Cabrera”, CSIC, Madrid, Spain.
    Berntsson, Ronnie P-A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria2024Inngår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikkel-id 1343Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The bacterial cell-wall peptidoglycan is made of glycan strands crosslinked by short peptide stems. Crosslinks are catalyzed by DD-transpeptidases (4,3-crosslinks) and LD-transpeptidases (3,3-crosslinks). However, recent research on non-model species has revealed novel crosslink types, suggesting the existence of uncharacterized enzymes. Here, we identify an LD-transpeptidase, LDTGo, that generates 1,3-crosslinks in the acetic-acid bacterium Gluconobacter oxydans. LDTGo-like proteins are found in Alpha- and Betaproteobacteria lacking LD3,3-transpeptidases. In contrast with the strict specificity of typical LD- and DD-transpeptidases, LDTGo can use non-terminal amino acid moieties for crosslinking. A high-resolution crystal structure of LDTGo reveals unique features when compared to LD3,3-transpeptidases, including a proline-rich region that appears to limit substrate access, and a cavity accommodating both glycan chain and peptide stem from donor muropeptides. Finally, we show that DD-crosslink turnover is involved in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between distinct crosslinking mechanisms in maintaining cell wall integrity in G. oxydans.

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  • 164.
    Espaillat, Akbar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Carrasco-Lopez, Cesar
    Bernardo-Garcia, Noelia
    Pietrosemoli, Natalia
    Otero, Lisandro H.
    Alvarez, Laura
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    de Pedro, Miguel A.
    Pazos, Florencio
    Davis, Brigid M.
    Waldor, Matthew K.
    Hermoso, Juan A.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Structural basis for the broad specificity of a new family of amino-acid racemases2014Inngår i: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 70, s. 79-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Broad-spectrum amino-acid racemases (Bsrs) enable bacteria to generate noncanonical D-amino acids, the roles of which in microbial physiology, including the modulation of cell-wall structure and the dissolution of biofilms, are just beginning to be appreciated. Here, extensive crystallographic, mutational, biochemical and bioinformatic studies were used to define the molecular features of the racemase BsrV that enable this enzyme to accommodate more diverse substrates than the related PLP-dependent alanine racemases. Conserved residues were identified that distinguish BsrV and a newly defined family of broad-spectrum racemases from alanine racemases, and these residues were found to be key mediators of the multispecificity of BrsV. Finally, the structural analysis of an additional Bsr that was identified in the bioinformatic analysis confirmed that the distinguishing features of BrsV are conserved among Bsr family members.

  • 165.
    Espaillat, Akbar
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Carrasco-López, Cesar
    Department of Crystallography & Structural Biology, Institute of Physical-Chemistry “Rocasolano”, CSIC, Madrid, Spain.
    Bernardo-García, Noelia
    Department of Crystallography & Structural Biology, Institute of Physical-Chemistry “Rocasolano”, CSIC, Madrid, Spain.
    Rojas-Altuve, Alzoray
    Department of Crystallography & Structural Biology, Institute of Physical-Chemistry “Rocasolano”, CSIC, Madrid, Spain.
    Klett, Javier
    Centro de Biología Molecular Severo Ochoa, CSIC, Madrid, Spain.
    Morreale, Antonio
    Centro de Biología Molecular Severo Ochoa, CSIC, Madrid, Spain.
    Hermoso, Juan A.
    Department of Crystallography & Structural Biology, Institute of Physical-Chemistry “Rocasolano”, CSIC, Madrid, Spain.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Binding of non-canonical peptidoglycan controls Vibrio cholerae broad spectrum racemase activity2021Inngår i: Computational and Structural Biotechnology Journal, E-ISSN 2001-0370, Vol. 19, s. 1119-1126Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Broad-spectrum amino acid racemases (Bsrs) enable bacteria to generate non-canonical D-amino acids (NCDAAs), whose roles and impact on microbial physiology, including modulation of cell wall structure and dissolution of biofilms, are just beginning to be appreciated. Here we used a diverse array of structural, biochemical and molecular simulation studies to define and characterize how BsrV is post-translationally regulated. We discovered that contrary to Vibrio cholerae alanine racemase AlrV highly compacted active site, BsrV’s is broader and can be occupied by cell wall stem peptides. We found that peptidoglycan peptides modified with NCDAAs are better stabilized by BsrV’s catalytic cavity and show better inhibitory capacity than canonical muropeptides. Notably, BsrV binding and inhibition can be recapitulated by undigested peptidoglycan sacculi as it exists in the cell. Docking simulations of BsrV binding the peptidoglycan polymer generate a model where the peptide stems are perfectly accommodated and stabilized within each of the dimeŕs active sites. Taking these biochemical and structural data together, we propose that inhibition of BsrV by peptidoglycan peptides underlies a negative regulatory mechanism to avoid excessive NCDAA production. Our results collectively open the door to use “à la carte” synthetic peptides as a tool to modulate DAAs production of Bsr enzymes.

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  • 166.
    Espaillat, Akbar
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Forsmo, Oskar
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    El Biari, Khouzaima
    Björk, Rafael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lemaitre, Bruno
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Canada, Francisco Javier
    de Pedro, Miguel A.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chemometric Analysis of Bacterial Peptidoglycan Reveals Atypical Modifications That Empower the Cell Wall against Predatory Enzymes and Fly Innate Immunity2016Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, nr 29, s. 9193-9204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Peptidoglycan is a fundamental structure for most bacteria. It contributes to the cell morphology and provides cell wall integrity against environmental insults. While several studies have reported a significant degree of variability in the chemical composition and organization of peptidoglycan in the domain Bacteria, the real diversity of this polymer is far from fully explored. This work exploits rapid ultraperformance liquid chromatography and multivariate data analysis to uncover peptidoglycan chemical diversity in the Class Alphaproteobacteria, a group of Gram negative bacteria that are highly heterogeneous in terms of metabolism, morphology and life-styles. Indeed, chemometric analyses revealed novel peptidoglycan structures conserved in Acetobacteria: amidation at the alpha-(L)-carboxyl of meso-diaminopimelic acid and the presence of muropeptides cross-linked by (1-3) L-Ala-D-(meso)diaminopimelate cross-links. Both structures are growth-controlled modifications that influence sensitivity to Type VI secretion system peptidoglycan endopeptidases and recognition by the Drosophila innate immune system, suggesting relevant roles in the environmental adaptability of these bacteria. Collectively our findings demonstrate the discriminative power of chemometric tools on large cell wall-chromatographic data sets to discover novel peptidoglycan structural properties in bacteria.

  • 167. Evans, Margery L.
    et al.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Taylor, Jonathan D.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Götheson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Li, Fei
    Koch, Marion
    Sefer, Lea
    Matthews, Steve J.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The Bacterial Curli System Possesses a Potent and Selective Inhibitor of Amyloid Formation2015Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 57, nr 3, s. 445-455Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Summary Curli are extracellular functional amyloids that are assembled by enteric bacteria during biofilm formation and host colonization. An efficient secretion system and chaperone network ensures that the major curli fiber subunit, CsgA, does not form intracellular amyloid aggregates. We discovered that the periplasmic protein CsgC was a highly effective inhibitor of CsgA amyloid formation. In the absence of CsgC, CsgA formed toxic intracellular aggregates. In vitro, CsgC inhibited CsgA amyloid formation at substoichiometric concentrations and maintained CsgA in a non-β-sheet-rich conformation. Interestingly, CsgC inhibited amyloid assembly of human α-synuclein, but not Aβ42, in vitro. We identified a common D-Q-Φ-X0,1-G-K-N-ζ-E motif in CsgC client proteins that is not found in Aβ42. CsgC is therefore both an efficient and selective amyloid inhibitor. Dedicated functional amyloid inhibitors may be a key feature that distinguishes functional amyloids from disease-associated amyloids.

  • 168.
    Fahlgren, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Avican, Kemal
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Westermark, Linda
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Nordfelth, Roland
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis2014Inngår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, nr 8, s. 3471-3482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Yersiniosis is a human disease caused by the bacterium Yersinia pseudotuberculosis or Yersinia enterocolitica. The infection is usually resolved but can lead to postinfectious sequelae, including reactive arthritis and erythema nodosum. The commonly used Yersinia mouse infection model mimics acute infection in humans to some extent but leads to systemic infection and eventual death. Here, we analyzed sublethal infection doses of Y. pseudotuberculosis in mice in real time using bioluminescent imaging and found that infections using these lower doses result in extended periods of asymptomatic infections in a fraction of mice. In a search for the site for bacterial persistence, we found that the cecum was the primary colonization site and was the site where the organism resided during a 115-day infection period. Persistent infection was accompanied by sustained fecal shedding of cultivable bacteria. Cecal patches were identified as the primary site for cecal colonization during persistence. Y. pseudotuberculosis bacteria were present in inflammatory lesions, in localized foci, or as single cells and also in neutrophil exudates in the cecal lumen. The chronically colonized cecum may serve as a reservoir for dissemination of infection to extraintestinal sites, and a chronic inflammatory state may trigger the onset of postinfectious sequelae. This novel mouse model for bacterial persistence in cecum has potential as an investigative tool to unveil a deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection.

  • 169.
    Fahlgren, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Westermark, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Akopyan, Karen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Cell type-specific effects of Yersinia pseudotuberculosis virulence effectors2009Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 11, nr 12, s. 1750-1767Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One important feature of Yersinia pseudotuberculosis that enables resistance against the host immune defence is delivery of the antiphagocytic effectors YopH and YopE into phagocytic cells. The tyrosine phosphatase YopH influences integrin signalling, and YopE impairs cytoskeletal dynamics by inactivating Rho GTPases. Here, we report the impact of these effectors on internalization by dendritic cells (DCs), which internalize antigens to orchestrate host immune responses. We found that this pathogen resists internalization by DCs via YopE. YopH that is important for blocking phagocytosis by macrophages and neutrophils and which is also present inside the DCs does not contribute to the resistance. However, the YopH targets Fyb and p130Cas show higher expression levels in macrophages than in DCs. Furthermore, live cell microscopy revealed that the cells internalize Y. pseudotuberculosis in different ways: the macrophages utilize a locally restricted receptor-mediated zipper mechanism, whereas DCs utilize macropinocytosis involving constitutive ruffling that randomly catches bacteria into membrane folds. We conclude that YopH impacts early phagocytic signalling from the integrin receptor to which the bacterium binds and that this tight receptor-mediated stimulation is absent in DC macropinocytosis. Inactivation of cytoskeletal dynamics by YopE affects ruffling activity and hence also internalization. The different modes of internalization can be coupled to the major functions of these respective cell types: elimination by phagocytosis and antigen sampling.

  • 170.
    Fan, Mingzhen
    et al.
    Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland.
    Kiefer, Patrick
    Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
    Charki, Paul
    Institute of Organic Chemistry, University of Würzburg, Würzburg, Germany.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Seibel, Jürgen
    Institute of Organic Chemistry, University of Würzburg, Würzburg, Germany.
    Vorholt, Julia A.
    Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
    Hilbi, Hubert
    Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland.
    The Legionella autoinducer LAI-1 is delivered by outer membrane vesicles to promote interbacterial and interkingdom signaling2023Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 299, nr 12, artikkel-id 105376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Legionella pneumophila is an environmental bacterium, which replicates in amoeba but also in macrophages, and causes a life-threatening pneumonia called Legionnaires’ disease. The opportunistic pathogen employs the α-hydroxy-ketone compound Legionella autoinducer-1 (LAI-1) for intraspecies and interkingdom signaling. LAI-1 is produced by the autoinducer synthase Legionella quorum sensing A (LqsA), but it is not known, how LAI-1 is released by the pathogen. Here, we use a Vibrio cholerae luminescence reporter strain and liquid chromatography-tandem mass spectrometry to detect bacteria-produced and synthetic LAI-1. Ectopic production of LqsA in Escherichia coli generated LAI-1, which partitions to outer membrane vesicles (OMVs) and increases OMV size. These E. coli OMVs trigger luminescence of the V. cholerae reporter strain and inhibit the migration of Dictyostelium discoideum amoeba. Overexpression of lqsA in L. pneumophila under the control of strong stationary phase promoters (PflaA or P6SRNA), but not under control of its endogenous promoter (PlqsA), produces LAI-1, which is detected in purified OMVs. These L. pneumophila OMVs trigger luminescence of the Vibrio reporter strain and inhibit D. discoideum migration. L. pneumophila OMVs are smaller upon overexpression of lqsA or upon addition of LAI-1 to growing bacteria, and therefore, LqsA affects OMV production. The overexpression of lqsA but not a catalytically inactive mutant promotes intracellular replication of L. pneumophila in macrophages, indicating that intracellularly produced LA1-1 modulates the interaction in favor of the pathogen. Taken together, we provide evidence that L. pneumophila LAI-1 is secreted through OMVs and promotes interbacterial communication and interactions with eukaryotic host cells.

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  • 171.
    Farag, Salah
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Francis, Monika K.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Gurung, Jyoti M.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Stenlund, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Swedish Metabolomics Centre (SMC), Umeå, Sweden.
    Francis, Matthew S
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Nadeem, Aftab
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Macrophage innate immune responses delineate between defective translocon assemblies produced by Yersinia pseudotuberculosis YopD mutants2023Inngår i: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 14, nr 1, artikkel-id 2249790Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Translocon pores formed in the eukaryotic cell membrane by a type III secretion system facilitate the translocation of immune-modulatory effector proteins into the host cell interior. The YopB and YopD proteins produced and secreted by pathogenic Yersinia spp. harboring a virulence plasmid-encoded type III secretion system perform this pore-forming translocator function. We had previously characterized in vitro T3SS function and in vivo pathogenicity of a number of strains encoding sited-directed point mutations in yopD. This resulted in the classification of mutants into three different classes based upon the severity of the phenotypic defects. To investigate the molecular and functional basis for these defects, we explored the effectiveness of RAW 264.7 cell line to respond to infection by representative YopD mutants of all three classes. Signature cytokine profiles could separate the different YopD mutants into distinct categories. The activation and suppression of certain cytokines that function as central innate immune response modulators correlated well with the ability of mutant bacteria to alter anti-phagocytosis and programmed cell death pathways. These analyses demonstrated that sub-optimal translocon pores impact the extent and magnitude of host cell responsiveness, and this limits the capacity of pathogenic Yersinia spp. to fortify against attack by both early and late arms of the host innate immune response.

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  • 172.
    Farag, Salah
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Francis, Monika K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nadeem, Aftab
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Francis, Matthew S
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Impact of Defective Translocon Assemblies on Hierarchal Yop Effector Translocation by Yersinia pseudotuberculosisManuskript (preprint) (Annet vitenskapelig)
  • 173. Fasullo, Michael
    et al.
    Tsaponina, Olga
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sun, Mingzeng
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Elevated dNTP levels suppress hyper-recombination in Saccharomyces cerevisiae S-phase checkpoint mutants2010Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 38, nr 4, s. 1195-1203Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MEC1, the essential yeast homolog of the human ATR/ATM genes, controls the S-phase checkpoint and prevents replication fork collapse at slow zones of DNA replication. The viability of hypomorphic mec1-21 is reduced in the rad52 mutant, defective in homologous recombination, suggesting that replication generates recombinogenic lesions. We previously observed a 6-, 10- and 30-fold higher rate of spontaneous sister chromatid exchange (SCE), heteroallelic recombination and translocations, respectively, in mec1-21 mutants compared to wild-type. Here we report that the hyper-recombination phenotype correlates with lower deoxyribonucleoside triphosphate (dNTP) levels, compared to wild-type. By introducing a dun1 mutation, thus eliminating inducible expression of ribonucleotide reductase in mec1-21, rates of spontaneous SCE increased 15-fold above wild-type. All the hyper-recombination phenotypes were reduced by SML1 deletions, which increase dNTP levels. Measurements of dNTP pools indicated that, compared to wild-type, there was a significant decrease in dNTP levels in mec1-21, dun1 and mec1-21 dun1, while the dNTP levels of mec1-21 sml1, mec1-21 dun1 sml1 and sml1 mutants were approximately 2-fold higher. Interestingly, higher dNTP levels in mec1-21 dun1 sml1 correlate with approximately 2-fold higher rate of spontaneous mutagenesis, compared to mec1-21 dun1. We suggest that higher dNTP levels in specific checkpoint mutants suppress the formation of recombinogenic lesions.

  • 174.
    Fei, Keke
    et al.
    Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
    Chao, Hong-Jun
    Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Hu, Yangbo
    Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Francis, Matthew S
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Chen, Shiyun
    Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    CpxR regulates the Rcs phosphorelay system in controlling the Ysc-Yop type III secretion system in Yersinia pseudotuberculosis2021Inngår i: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 167, nr 1, artikkel-id 000998Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The CpxRA two-component regulatory system and the Rcs phosphorelay system are both employed by the Enterobacteriaceae family to preserve bacterial envelope integrity and function when growing under stress. Although both systems regulate several overlapping physiological processes, evidence demonstrating a molecular connection between Cpx and Rcs signalling outputs is scarce. Here, we show that CpxR negatively regulates the transcription of the rcsB gene in the Rcs phosphorelay system in Yersinia pseudotuberculosis. Interestingly, transcription of rcsB is under the control of three promoters, which were all repressed by CpxR. Critically, synthetic activation of Cpx signalling through mislocalization of the NlpE lipoprotein to the inner membrane resulted in an active form of CpxR that repressed activity of rcsB promoters. On the other hand, a site-directed mutation of the phosphorylation site at residue 51 in CpxR generated an inactive non-phosphorylated variant that was unable to regulate output from these rcsB promoters. Importantly, CpxR-mediated inhibition of rcsB transcription in turn restricted activation of the Ysc-Yop type III secretion system (T3SS). Moreover, active CpxR blocks zinc-mediated activation of Rcs signalling and the subsequent activation of lcrF transcription. Our results demonstrate a novel regulatory cascade linking CpxR-RcsB-LcrF to control production of the Ysc-Yop T3SS.

  • 175.
    Fei, Keke
    et al.
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Yan, Huan
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Zeng, Xiaoyan
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Huang, Shaojia
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Tang, Wei
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Francis, Matthew S.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chen, Shiyun
    CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    Hu, Yangbo
    State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
    LcrQ coordinates with the YopD-LcrH complex to repress lcrF expression and control type III secretion by Yersinia pseudotuberculosis2021Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 12, nr 3, artikkel-id e0145721Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human-pathogenic Yersinia species employ a plasmid-encoded type III secretion system (T3SS) to negate immune cell function during infection. A critical element in this process is the coordinated regulation of T3SS gene expression, which involves both transcriptional and posttranscriptional mechanisms. LcrQ is one of the earliest identified negative regulators of Yersinia T3SS, but its regulatory mechanism is still unclear. In a previous study, we showed that LcrQ antagonizes the activation role played by the master transcriptional regulator LcrF. In this study, we confirm that LcrQ directly interacts with LcrH, the chaperone of YopD, to facilitate the negative regulatory role of the YopD-LcrH complex in repressing lcrF expression at the posttranscriptional level. Negative regulation is strictly dependent on the YopD-LcrH complex, more so than on LcrQ. The YopD-LcrH complex helps to retain cytoplasmic levels of LcrQ to facilitate the negative regulatory effect. Interestingly, RNase E and its associated protein RhlB participate in this negative regulatory loop through a direct interaction with LcrH and LcrQ. Hence, we present a negative regulatory loop that physically connects LcrQ to the posttranscriptional regulation of LcrF, and this mechanism incorporates RNase E involved in mRNA decay.

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  • 176. Fernebro, Jenny
    et al.
    Blomberg, Christel
    Morfeldt, Eva
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Normark, Staffan
    Normark, Birgitta Henriques
    The influence of in vitro fitness defects on pneumococcal ability to colonize and to cause invasive disease.2008Inngår i: BMC Microbiology, E-ISSN 1471-2180, Vol. 8, s. 65-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Streptococcus pneumoniae is a genetically diverse major human pathogen, yet a common colonizer of the nasopharynx. Here we analyzed the influence of defects affecting in vitro growth rate, on the ability of S. pneumoniae to colonize and to cause invasive disease in vivo. RESULTS: Of eleven different clinical isolates one serotype 14 carrier isolate showed a significantly longer generation time as compared to other isolates, and was severely attenuated in mice. To directly investigate the impact of growth rate on virulence, a panel of mutants in five non-essential housekeeping genes was constructed in the virulent TIGR4 background by insertion-deletion mutagenesis. Three of these mutants (ychF, hemK and yebC) were, to different degrees, growth defective, and showed a reduced invasiveness in an intranasal murine challenge model that correlated to their in vitro growth rate, but remained capable of colonizing the upper airways. The growth defect, as well as virulence defect of the hemK insertion-deletion mutant, was mediated by polarity effects on the downstream yrdC gene, encoding a probable chaperone in ribosome assembly. CONCLUSION: We conclude that large fitness defects are needed to completely prevent pneumococci from causing invasive disease after intranasal challenge. However, even severe growth defects still allow pneumococci to persistently colonize the upper airways.

  • 177.
    Fernández, Leyden
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Rosvall, Martin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Avican, Kemal
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Co-PATHOgenex web application for assessing complex stress responses in pathogenic bacteria2024Inngår i: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, nr 1, artikkel-id e02781-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pathogenic bacteria encounter various stressors while residing in the host. They respond through intricate mechanisms of gene expression regulation, ensuring their survival and adaptation. Understanding how bacteria adapt to different stress conditions through regulatory processes of specific genes requires exploring complex transcriptional responses using gene co-expression networks. We employed a large transcriptome data set comprising 32 diverse human bacterial pathogens exposed to the same 11 host-mimicking stress conditions. Using the weighted gene co-expression network analysis algorithm, we generated bacterial gene co-expression networks. By associating modular eigengene expression with specific stress conditions, we identified gene co-expression modules and stress-specific stimulons, including genes with unique expression patterns under specific stress conditions. Suggesting a new potential role of the frm operon in responding to bile stress in enteropathogenic bacteria demonstrates the effectiveness of our approach. We also revealed the regulation of streptolysin S genes, involved in the production, processing, and export of streptolysin S, a toxin responsible for the beta-hemolytic phenotype of group A Streptococcus. In a comparative analysis of stress responses in three Escherichia coli strains from the core transcriptome, we revealed shared and unique expression patterns across the strains, offering insights into convergent and divergent stress responses. To help researchers perform similar analyses, we created the user-friendly web application Co-PATHOgenex. This tool aids in deepening our understanding of bacterial adaptation to stress conditions and in deciphering complex transcriptional responses of bacterial pathogens.IMPORTANCEUnveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition. Unveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition.

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  • 178.
    Figueroa-Cuilan, Wanda M.
    et al.
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Irazoki, Oihane
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Feeley, Marissa
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Smith, Erika
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Nguyen, Trung
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Goley, Erin D.
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Quantitative analysis of morphogenesis and growth dynamics in an obligate intracellular bacterium2023Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 34, nr 7, artikkel-id ar69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obligate intracellular bacteria of the order Rickettsiales include important human pathogens. However, our understanding of the biology of Rickettsia species is limited by challenges imposed by their obligate intracellular lifestyle. To overcome this roadblock, we developed methods to assess cell wall composition, growth, and morphology of Rickettsia parkeri, a human pathogen in the spotted fever group of the Rickettsia genus. Analysis of the cell wall of R. parkeri revealed unique features that distinguish it from free-living alphaproteobacteria. Using a novel fluorescence microscopy approach, we quantified R. parkeri morphology in live host cells and found that the fraction of the population undergoing cell division decreased over the course of infection. We further demonstrated the feasibility of localizing fluorescence fusions, for example, to the cell division protein ZapA, in live R. parkeri for the first time. To evaluate population growth kinetics, we developed an imaging-based assay that improves on the throughput and resolution of other methods. Finally, we applied these tools to quantitatively demonstrate that the actin homologue MreB is required for R. parkeri growth and rod shape. Collectively, a toolkit was developed of high-throughput, quantitative tools to understand growth and morphogenesis of R. parkeri that is translatable to other obligate intracellular bacteria.

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  • 179.
    Filcek, Kimberly
    et al.
    University of Maryland, Department of Microbial Pathogenesis.
    Vielfort, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Muraleedharan, Samada
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael
    Duke University, Department of Molecular Genetics and Microbiology.
    Bavoil, Patrik
    University of Maryland, Department of Microbial Pathogenesis.
    Sixt, Barbara Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America.
    Insertional mutagenesis in the zoonotic pathogen Chlamydia caviae2019Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 14, nr 11, artikkel-id e0224324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ability to introduce targeted genetic modifications in microbial genomes has revolutionized our ability to study the role and mode of action of individual bacterial virulence factors. Although the fastidious lifestyle of obligate intracellular bacterial pathogens poses a technical challenge to such manipulations, the last decade has produced significant advances in our ability to conduct molecular genetic analysis in Chlamydia trachomatis, a major bacterial agent of infertility and blindness. Similar approaches have not been established for the closely related veterinary Chlamydia spp., which cause significant economic damage, as well as rare but potentially life-threatening infections in humans. Here we demonstrate the feasibility of conducting site-specific mutagenesis for disrupting virulence genes in Ccaviae, an agent of guinea pig inclusion conjunctivitis that was recently identified as a zoonotic agent in cases of severe community-acquired pneumonia. Using this approach, we generated Ccaviae mutants deficient for the secreted effector proteins IncA and SinC. We demonstrate that Ccaviae IncA plays a role in mediating fusion of the bacteria-containing vacuoles inhabited by Ccaviae. Moreover, using a chicken embryo infection model, we provide first evidence for a role of SinC in Ccaviae virulence in vivo.

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  • 180. Flentie, Kelly
    et al.
    Harrison, Gregory A.
    Tükenmez, Hasan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Livny, Jonathan
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sarkar, Souvik
    Zhu, Dennis X.
    Kinsella, Rachel L.
    Weiss, Leslie A.
    Solomon, Samantha D.
    Schene, Miranda E.
    Hansen, Mette R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cairns, Andrew G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Kulén, Martina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wixe, Torbjörn
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Anders E. G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Larsson, Christer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Stallings, Christina L.
    Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis2019Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 21, s. 10510-10517Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

  • 181. Fleurie, Aurore
    et al.
    Zoued, Abdelrahim
    Alvarez, Laura
    Hines, Kelly M.
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Xu, Libin
    Davis, Brigid M.
    Waldor, Matthew K.
    A Vibrio cholerae BolA-Like Protein Is Required for Proper Cell Shape and Cell Envelope Integrity2019Inngår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, nr 4, artikkel-id e00790-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BolA family proteins are conserved in Gram-negative bacteria and many eukaryotes. While diverse cellular phenotypes have been linked to this protein family, the molecular pathways through which these proteins mediate their effects are not well described. Here, we investigated the roles of BolA family proteins in Vibrio cholerae, the cholera pathogen. Like Escherichia coli, V. cholerae encodes two BolA proteins, BolA and IbaG. However, in marked contrast to E. coli, where bolA is linked to cell shape and ibaG is not, in V. cholerae, bolA mutants lack morphological defects, whereas ibaG proved critical for the generation and/or maintenance of the pathogen's morphology. Notably, the bizarre-shaped, multipolar, elongated, and wide cells that predominated in exponential-phase Delta ibaG V. cholerae cultures were not observed in stationary-phase cultures. The V. cholerae Delta ibaG mutant exhibited increased sensitivity to cell envelope stressors, including cell wall-acting antibiotics and bile, and was defective in intestinal colonization. Delta ibaG V. cholerae had reduced peptidoglycan and lipid II and altered outer membrane lipids, likely contributing to the mutant's morphological defects and sensitivity to envelope stressors. Transposon insertion sequencing analysis of ibaG's genetic interactions suggested that ibaG is involved in several processes involved in the generation and homeostasis of the cell envelope. Furthermore, copurification studies revealed that IbaG interacts with proteins containing iron-sulfur clusters or involved in their assembly. Collectively, our findings suggest that V. cholerae IbaG controls cell morphology and cell envelope integrity through its role in biogenesis or trafficking of iron-sulfur cluster proteins. IMPORTANCE BolA-like proteins are conserved across prokaryotes and eukaryotes. These proteins have been linked to a variety of phenotypes, but the pathways and mechanisms through which they act have not been extensively characterized. Here, we unraveled the role of the BolA-like protein IbaG in the cholera pathogen Vibrio cholerae. The absence of IbaG was associated with dramatic changes in cell morphology, sensitivity to envelope stressors, and intestinal colonization defects. IbaG was found to be required for biogenesis of several components of the V. cholerae cell envelope and to interact with numerous iron-sulfur cluster-containing proteins and factors involved in their assembly. Thus, our findings suggest that IbaG governs V. cholerae cell shape and cell envelope homeostasis through its effects on iron-sulfur proteins and associated pathways. The diversity of processes involving ironsulfur-containing proteins is likely a factor underlying the range of phenotypes associated with BolA family proteins.

  • 182.
    Flodbring Larsson, Per
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Karlsson, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden.
    Sarwar, Martuza
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Miftakhova, Regina R.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wang, Tianyan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Khaja, Azharuddin Sajid Syed
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Semenas, Julius
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Chen, Sa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Hedblom, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden.
    Ali, Amjad
    Ekström-Holka, Kristina
    Simoulis, Athanasios
    Kumar, Anjani
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gjörloff Wingren, Anette
    Robinson, Brian
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Mongan, Nigel P.
    Heery, David M.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Grundström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ødum, Niels
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden; Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer2022Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.

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  • 183. Floyd, Kyle A.
    et al.
    Moore, Jessica L.
    Eberly, Allison R.
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Shaffer, Carrie L.
    Zaver, Himesh
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Skaar, Eric P.
    Caprioli, Richard M.
    Hadjifrangiskou, Maria
    Adhesive Fiber Stratification in Uropathogenic Escherichia coli Biofilms Unveils Oxygen-Mediated Control of Type 1 Pili2015Inngår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, nr 3, artikkel-id e1004697Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bacterial biofilms account for a significant number of hospital-acquired infections and complicate treatment options, because bacteria within biofilms are generally more tolerant to antibiotic treatment. This resilience is attributed to transient bacterial subpopulations that arise in response to variations in the microenvironment surrounding the biofilm. Here, we probed the spatial proteome of surface-associated single-species biofilms formed by uropathogenic Escherichia coli (UPEC), the major causative agent of community-acquired and catheter-associated urinary tract infections. We used matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) to analyze the spatial proteome of intact biofilms in situ. MALDI-TOF IMS revealed protein species exhibiting distinct localizations within surface-associated UPEC biofilms, including two adhesive fibers critical for UPEC biofilm formation and virulence: type 1 pili (Fim) localized exclusively to the air-exposed region, while curli amyloid fibers localized to the air-liquid interface. Comparison of cells grown aerobically, fermentatively, or utilizing an alternative terminal electron acceptor showed that the phase-variable fim promoter switched to the "FF" orientation under oxygen-deplete conditions, leading to marked reduction of type 1 pili on the bacterial cell surface. Conversely, S pili whose expression is inversely related to fim expression were upregulated under anoxic conditions. Tethering the fim promoter in the "ON" orientation in anaerobically grown cells only restored type 1 pili production in the presence of an alternative terminal electron acceptor beyond oxygen. Together these data support the presence of at least two regulatory mechanisms controlling fim expression in response to oxygen availability and may contribute to the stratification of extracellular matrix components within the biofilm. MALDI IMS facilitated the discovery of these mechanisms, and we have demonstrated that this technology can be used to interrogate subpopulations within bacterial biofilms.

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  • 184.
    Fluckiger, Aurélie
    et al.
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Daillere, Romain
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; everImmune, Gustave Roussy Cancer Center, Villejuif, France.
    Sassi, Mohamed
    Université Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France.
    Sixt, Barbara Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Liu, Peng
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Loos, Friedemann
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France.
    Richard, Corentin
    Research Platform in Biological Oncology, Dijon, France; GIMI Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy-Franche Comté, Dijon, France.
    Rabu, Catherine
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Alou, Maryam Tidjani
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Goubet, Anne-Gaelle
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Lemaitre, Fabien
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; everImmune, Gustave Roussy Cancer Center, Villejuif, France.
    Ferrere, Gladys
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Derosa, Lisa
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Université Paris-Saclay, Villejuif, F-94805, France.
    Duong, Connie P. M.
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France.
    Messaoudene, Meriem
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    Gagne, Andreanne
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    Joubert, Philippe
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada.
    De Sordi, Luisa
    Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France; Sorbonne Université, Centre de Recherche Saint Antoine, INSERM UMRS_938, Paris, France.
    Debarbieux, Laurent
    Bacteriophage, Bacterium, Host Laboratory, Institut Pasteur, F-75015 Paris, France.
    Simon, Sylvain
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Scarlata, Clara-Maria
    Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France.
    Ayyoub, Maha
    Cancer Research Centre of Toulouse, INSERM UMR 1037, 31037 Toulouse, France; Université Toulouse III Paul Sabatier, 31330 Toulouse, France; Institut Universitaire du Cancer de Toulouse-Oncopole, 31100 Toulouse, France.
    Palermo, Belinda
    Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Facciolo, Francesco
    Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Boidot, Romain
    Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Anticancer Center, UNICANCER, Dijon, France.
    Wheeler, Richard
    Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France.
    Boneca, Ivo Gomperts
    Institut Pasteur, Unit Biology and Genetics of the Bacterial Cell Wall, Paris, France.
    Sztupinszki, Zsofia
    Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA.
    Papp, Krisztian
    Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.
    Csabai, Istvan
    Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.
    Pasolli, Edoardo
    Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy.
    Segata, Nicola
    Department CIBIO, University of Trento, Trento, Italy.
    Lopez-Otin, Carlos
    Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France; Sorbonne Université, Paris, France; Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
    Szallasi, Zoltan
    Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA; Danish Cancer Society Research Center, Copenhagen, Denmark; MTA-SE-NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
    Andre, Fabrice
    Department of Cancer Medicine, Breast Cancer Committee, Gustave Roussy, Villejuif, France; INSERM Unit 981, Gustave Roussy, Villejuif, France.
    Iebba, Valerio
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Department of Medical Sciences, University of Trieste, 34137 Trieste, Italy.
    Quiniou, Valentin
    AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France; Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France.
    Klatzmann, David
    AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center in Biotherapy (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), F-75651, Paris, France; Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75651, Paris, France.
    Boukhalil, Jacques
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Khelaifia, Saber
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Raoult, Didier
    UMR MEPHI, Aix-Marseille Université, IRD, AP-HM, Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, 13385, Marseille cedex 05, France.
    Albiges, Laurence
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France.
    Escudier, Bernard
    ustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; INSERM U981, GRCC, Villejuif, France.
    Eggermont, Alexander
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Princess Maxima Center, CS 3584 Utrecht, the Netherlands.
    Mami-Chouaib, Fathia
    INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Fac. de Médecine - Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
    Nistico, Paola
    Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy; Thoracic Surgery Unit, Department of Surgical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
    Ghiringhelli, Francois
    Department of Medical Oncology, Center GF Leclerc, Dijon, France.
    Routy, Bertrand
    Institut Universitaire de Cardiologie et de Pneumologie de Québec, Research Center and Department of Cytology and Pathology, Québec City, Québec, Canada; Division d'Hémato-Oncologie, Département de Médicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
    Labarriere, Nathalie
    CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France; LabEx IGO “Immunotherapy, Graft, Oncology,” Nantes, France.
    Cattoir, Vincent
    Université Rennes 1, Laboratoire de Biochimie Pharmaceutique, Inserm U1230 - UPRES EA 2311, Rennes, France; CHU de Rennes - Hôpital Ponchaillou, Service de Bactériologie-Hygiène Hospitalière, Rennes, France; CNR de la Résistance aux Antibiotiques (laboratoire associé 'Entérocoques'), Rennes, France..
    Kroemer, Guido
    Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM U1138, Paris, France; Université de Paris, Paris, France. Sorbonne Université, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China; Institut Universitaire de France, Paris, France.
    Zitvogel, Laurence
    Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U1015, Institut Gustave Roussy, Villejuif, France; Université Paris-Saclay, Villejuif, F-94805, France; Suzhou Institute for Systems Biology, Chinese Academy of Medical Sciences, Suzhou, China.
    Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage2020Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 369, nr 6506, s. 936-942Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.

  • 185. Foley, Daniel J.
    et al.
    Zinken, Sarah
    Corkery, Dale
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Laraia, Luca
    Pahl, Axel
    Wu, Yao-Wen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor2020Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, nr 30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.

    Fulltekst (pdf)
    fulltext
  • 186.
    Fonfara, Ines
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig, Germany.
    Le Rhun, Anaïs
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig, Germany.
    Chylinski, Krzysztof
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Deptartment of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Austria.
    Makarova, Kira S.
    Lécrivain, Anne-Laure
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bzdrenga, Janek
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Koonin, Eugene V.
    Charpentier, Emmanuelle
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig, Germany ; Hannover Medical School, Hannover, Germany .
    Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems2014Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr 4, s. 2577-2590Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The CRISPR-Cas-derived RNA-guided Cas9 endonuclease is the key element of an emerging promising technology for genome engineering in a broad range of cells and organisms. The DNA-targeting mechanism of the type II CRISPR-Cas system involves maturation of tracrRNA: crRNA duplex (dual-RNA), which directs Cas9 to cleave invading DNA in a sequence-specific manner, dependent on the presence of a Protospacer Adjacent Motif (PAM) on the target. We show that evolution of dual-RNA and Cas9 in bacteria produced remarkable sequence diversity. We selected eight representatives of phylogenetically defined type II CRISPR-Cas groups to analyze possible coevolution of Cas9 and dual-RNA. We demonstrate that these two components are interchangeable only between closely related type II systems when the PAM sequence is adjusted to the investigated Cas9 protein. Comparison of the taxonomy of bacterial species that harbor type II CRISPR-Cas systems with the Cas9 phylogeny corroborates horizontal transfer of the CRISPR-Cas loci. The reported collection of dual-RNA: Cas9 with associated PAMs expands the possibilities for multiplex genome editing and could provide means to improve the specificity of the RNA-programmable Cas9 tool.

    Fulltekst (pdf)
    fulltext
  • 187.
    Fonfara, Ines
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Richter, Hagen
    Bratovic, Majda
    Le Rhun, Anaïs
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    Charpentier, Emmanuelle
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
    The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA2016Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, nr 7600, s. 517-520Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CRISPR-Cas systems that provide defence against mobile genetic elements in bacteria and archaea have evolved a variety of mechanisms to target and cleave RNA or DNA(1). The well-studied types I, II and III utilize a set of distinct CRISPR-associated ( Cas) proteins for production of mature CRISPR RNAs (crRNAs) and interference with invading nucleic acids. In types I and III, Cas6 or Cas5d cleaves precursor crRNA (pre-crRNA)(2-5) and the mature crRNAs then guide a complex of Cas proteins ( Cascade-Cas3, type I; Csm or Cmr, type III) to target and cleave invading DNA or RNA(6-12). In type II systems, RNase III cleaves pre-crRNA base-paired with trans-activating crRNA (tracrRNA) in the presence of Cas9 (refs 13, 14). The mature tracrRNA-crRNA duplex then guides Cas9 to cleave target DNA15. Here, we demonstrate a novel mechanism in CRISPR-Cas immunity. We show that type V-A Cpf1 from Francisella novicida is a dual-nuclease that is specific to crRNA biogenesis and target DNA interference. Cpf1 cleaves pre-crRNA upstream of a hairpin structure formed within the CRISPR repeats and thereby generates intermediate crRNAs that are processed further, leading to mature crRNAs. After recognition of a 5'-YTN- 3' protospacer adjacent motif on the non-target DNA strand and subsequent probing for an eight-nucleotide seed sequence, Cpf1, guided by the single mature repeat-spacer crRNA, introduces double-stranded breaks in the target DNA to generate a 5' overhang(16). The RNase and DNase activities of Cpf1 require sequence- and structure-specific binding to the hairpin of crRNA repeats. Cpf1 uses distinct active domains for both nuclease reactions and cleaves nucleic acids in the presence of magnesium or calcium. This study uncovers a new family of enzymes with specific dual endoribonuclease and endonuclease activities, and demonstrates that type V- A constitutes the most minimalistic of the CRISPR- Cas systems so far described.

  • 188.
    Forslund, Anna-Lena
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Forsberg, Åke
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kuoppa, Kerstin
    FOI Swedish Defence Research Agency, Division of CBRN Defence and Security.
    Meibom, Karin L.
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Alkhuder, Khaled
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Dubail, Iharilalao
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Dupuis, Marion
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Charbit, Alain
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Hfq, a novel pleiotropic regulator of virulence-associated genes in Francisella tularensis2009Inngår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, nr 5, s. 1866-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Francisella tularensis is a highly infectious pathogen that infects animals and humans, causing tularemia. The ability to replicate within macrophages is central for virulence and relies on expression of genes located in the Francisella pathogenicity island (FPI), as well as expression of other genes. Regulation of FPI-encoded virulence gene expression in F. tularensis involves at least four regulatory proteins and is not fully understood. Here we studied the RNA-binding protein Hfq in F. tularensis and particularly the role that it plays as a global regulator of gene expression in stress tolerance and pathogenesis. We demonstrate that Hfq promotes resistance to several cellular stresses (including osmotic and membrane stresses). Furthermore, we show that Hfq is important for the ability of the F. tularensis vaccine strain LVS to induce disease and persist in organs of infected mice. We also demonstrate that Hfq is important for stress tolerance and full virulence in a virulent clinical isolate of F. tularensis, FSC200. Finally, microarray analyses revealed that Hfq regulates expression of numerous genes, including genes located in the FPI. Strikingly, Hfq negatively regulates only one of two divergently expressed putative operons in the FPI, in contrast to the other known regulators, which regulate the entire FPI. Hfq thus appears to be a new pleiotropic regulator of virulence in F. tularensis, acting mostly as a repressor, in contrast to the other regulators identified so far. Moreover, the results obtained suggest a novel regulatory mechanism for a subset of FPI genes.

  • 189.
    Forslund, Anna-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Salomonsson, Emelie Näslund
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Kuoppa, Kerstin
    Michell, Stephen
    Titball, Richard
    Oyston, Petra
    Noppa, Laila
    FOI.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Forsberg, Åke
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    The type IV pilin, PilA, is required for full virulence of Francisella tularensis subspecies tularensis2010Inngår i: BMC Microbiology, E-ISSN 1471-2180, Vol. 10, s. 227-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This suggests that expression and surface localisation of PilA contribute to virulence in the highly virulent type A strain, while PilT was dispensable for virulence in the mouse infection model.

  • 190.
    Francis, Matthew
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Secretion systems and metabolism in the pathogenic Yersiniae2011Inngår i: Stress response in pathogenic bacteria / [ed] Stephen P. Kidd, United Kingdom: CAB International , 2011, 1, s. 185-220Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    The genus Yersinia comprises 11 species, three of which have clear etiology for causing human disease (Y. pestis, Y. pseudotuberculosis and Y. enterocolitica). The obligate pathogen Y. pestis is the most infamous of these being the causal agent of plague, a bivalent disease that when left untreated is invariably fatal. The lifecycle of Y. pestis is complex, being dependent on two diverse hosts – the invertebrate flea Xenopsylla cheopis and a mammalian host (usually wild rodents). Although capable of catastrophic consequences, plague in humans is accidental – a consequence of being infected with Y. pestis via the bite of an infected flea that has been forced from its normal rodent host. In brief, the initial stage of disease presents as swollen lymph nodes (buboes) and is termed bubonic plague, whereas the second stage is a more vigorous systemic infection that results in bacterial colonization of multiple tissue organs including the lung. This form of disease is termed pneumonic plague; a highly contagious disease that enables bacteria to rapidly and effectively spread to new hosts via aerosol droplets. In light of this, global health organizations routinely list Y. pestis as a category A biowarfare agent. On the other hand, Y. pseudotuberculosis and Y. enterocolitica are essentially environmental bacteria that are capable of causing spasmodic enteric disease (known as yersiniosis) outbreaks linked to the ingestion of contaminated food or fluids. While these diseases cause gastrointestinal discomfort, they are usually self-limiting and rarely associated with systemic disease. In certain susceptible individuals however, chronic reactive arthritic sequelae can be attributed to these bacteria.

    On account of their ability to cause human disease, a prolific amount of information is available that describes these three human pathogens with respect to their ecology, epidemiology and the pathogenesis of disease. In contrast, very little information is available concerning the additional Yersinia species (Y. frederiksenii, Y. intermedia, Y. kristensenii, Y. bercovieri, Y. mollaretii, Y. rohdei, Y. ruckeri, Y. aleksiciae, Y. mexicana and Y. aldovae). However, they might still be clinically relevant given their propensity to harbour a moderate number of genes that encode for products known to be associated with pathogenicity by other non-Yersinia bacteria. It is at least well established that Y. ruckeri is the causative agent of yersiniosis in infected salmonid fish, although the pathogenic mechanisms are comparatively poorly understood.

    In the first part of this chapter, the presence of known and suggested protein secretion mechanisms in the Yersiniae are described. Where appropriate, these individual processes are briefly discussed in the context of their contribution to bacterial pathogenesis to help the reader gain an understanding of their physiological importance within the various unique environments of an infected host. As considerably more is known about the pathogenic mechanisms of human pathogenic Yersinia, these examples will dominate the discussion. Then, focus will turn to the consequences of adaptation of pathogenic Yersinia to their surrounding environment. Where possible, emphasis will be given to the crosstalk between metabolism and the temporal and spatial regulatory control of these important secretion systems. This connection ensures that Yersinia conserve their valuable energy reserves to maximize their survival in stressful environments and only synthesize energetically expensive virulence determinants, such as multi-component secretion systems, when they will have utmost benefit during host infections.

  • 191.
    Francis, Matthew
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The pathogenic Yersiniae: advances in the understanding of physiology and virulence2013Inngår i: Frontiers in Cellular and Infection Microbiology, ISSN 2235-2988, Vol. 3, nr 51, s. 2s. 1-2Artikkel, forskningsoversikt (Fagfellevurdert)
    Fulltekst (pdf)
    fulltext
  • 192.
    Francis, Matthew
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Aili, Margareta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wiklund, Magda-Lena
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    A study of the YopD-LcrH interaction from Yersinia pseudotuberculosis reveals a role for hydrophobic residues within the amphipathic domain of YopD2000Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 38, nr 1, s. 85-102Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The enteropathogen Yersinia pseudotuberculosis is a model system used to study the molecular mechanisms by which Gram-negative pathogens translocate effector proteins into target eukaryotic cells by a common type III secretion machine. Of the numerous proteins produced by Y. pseudotuberculosis that act in concert to establish an infection, YopD (Yersiniaouter protein D) is a crucial component essential for yop regulation and Yop effector translocation. In this study, we describe the mechanisms by which YopD functions to control these processes. With the aid of the yeast two-hybrid system, we investigated the interaction between YopD and the cognate chaperone LcrH. We confirmed that non-secreted LcrH is necessary for YopD stabilization before secretion, presumably by forming a complex with YopD in the bacterial cytoplasm. At least in yeast, this complex depends upon the N-terminal domain and a C-terminal amphipathic α-helical domain of YopD. Introduction of amino acid substitutions within the hydrophobic side of the amphipathic α-helix abolished the YopD–LcrH interaction, indicating that hydrophobic, as opposed to electrostatic, forces of attraction are important for this process. Suppressor mutations isolated within LcrH could compensate for defects in the amphipathic domain of YopD to restore binding. Isolation of LcrH mutants unable to interact with wild-type YopD revealed no single domain responsible for YopD binding. The YopD and LcrH mutants generated in this study will be relevant tools for understanding YopD function during a Yersinia infection.

  • 193.
    Francis, Matthew S
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Type III secretion chaperones: a molecular toolkit for all occasions2010Inngår i: Handbook of molecular chaperones: roles, structures and mechanisms / [ed] Piero Durante and Leandro Colucci, New York: Nova Science Publishers , 2010, 1, s. 79-148Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Common to many bacteria is the ability to establish a symbiotic relationship or to evade innate immune responses of an animal, plant, fish or insect host. Most often this capacity is mediated by a type III secretion system (T3SS). The function of these complex molecular machines is likened to a syringe-needle injection device that is dedicated to the translocation of effector proteins directly into target eukaryotic cells. Each translocated effector tends to possess a distinct enzymatic activity that aids in subverting host cell signaling for the benefit of the bacterium. Their translocation requires another class of secreted protein – the translocator – which form pores in the target eukaryotic cell plasma membrane through which the effectors may transit to gain entry into the cell interior. Most often, each secreted substrate requires a dedicated small, non-secreted cytoplasmic chaperone for their efficient secretion. Unlike traditional molecular chaperones, these specialized type III chaperones do not assist in protein folding and are not energized by ATP. Controversy still surrounds their primary role; as bodyguards to prevent premature aggregation or as pilots to direct substrate secretion through the correct T3SS. The later is supported by recent evidence that these chaperones can dock directly to the cytoplasmic face of the T3S machinery, possibly serving as a recognition motif for substrate secretion. Added to this functional complexity is their important contribution to system regulation, which can ultimately confer temporal order to substrate secretion. Moreover, some chaperones display a bewildering propensity to interact with several additional T3S-associated proteins – the relevance of which remains uncertain. Structural data has now appeared for several important type III chaperones, either alone or in complex with their cognate substrate. This is proving a fillip in our attempts to understand the mercurial ways in which these versatile proteins operate in nature. It is hoped that this article will provide information on type III chaperone function, as well as highlighting key recent advances in the field. May it also be a testament to the value of continued intense effort in unravelling the mysteries of type III chaperone biology.

    Fulltekst (pdf)
    Type III Secretion Chaperones
  • 194.
    Francis, Matthew S.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Aili, Margareta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wiklund, Magda-Lena
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wolf-Watz, Hans
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    A study of the YopD-LcrH interaction from Yersinia pseudotuberculosis reveals a role for hydrophobic residues within the amphipathic domain of YopD2000Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 38, nr 1, s. 85-102Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The enteropathogen Yersinia pseudotuberculosis is a model system used to study the molecular mechanisms by which Gram-negative pathogens translocate effector proteins into target eukaryotic cells by a common type III secretion machine. Of the numerous proteins produced by Y. pseudotuberculosis that act in concert to establish an infection, YopD (Yersinia outer protein D) is a crucial component essential for yop regulation and Yop effector translocation. In this study, we describe the mechanisms by which YopD functions to control these processes. With the aid of the yeast two-hybrid system, we investigated the interaction between YopD and the cognate chaperone LcrH. We confirmed that non-secreted LcrH is necessary for YopD stabilization before secretion, presumably by forming a complex with YopD in the bacterial cytoplasm. At least in yeast, this complex depends upon the N-terminal domain and a C-terminal amphipathic alpha-helical domain of YopD. Introduction of amino acid substitutions within the hydrophobic side of the amphipathic alpha-helix abolished the YopD-LcrH interaction, indicating that hydrophobic, as opposed to electrostatic, forces of attraction are important for this process. Suppressor mutations isolated within LcrH could compensate for defects in the amphipathic domain of YopD to restore binding. Isolation of LcrH mutants unable to interact with wild-type YopD revealed no single domain responsible for YopD binding. The YopD and LcrH mutants generated in this study will be relevant tools for understanding YopD function during a Yersinia infection.

  • 195.
    Francis, Matthew S
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Amer, Ayad A A
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Milton, Debra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Biological and Environmental Sciences, Troy University, Troy, AL, USA.
    Costa, Tiago R D
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Institute of Structural and Molecular Biology, University College London and Birkbeck, London, UK.
    Site-directed mutagenesis and its application in studying the interactions of T3S components2017Inngår i: Type 3 secretion systems: methods and protocols / [ed] Matthew L. Nilles and Danielle L. Jessen Condry, Humana Press, 2017, s. 11-31Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Type III secretion systems are a prolific virulence determinant among Gram-negative bacteria. They are used to paralyze the host cell, which enables bacterial pathogens to establish often fatal infections—unless an effective therapeutic intervention is available. However, as a result of a catastrophic rise in infectious bacteria resistant to conventional antibiotics, these bacteria are again a leading cause of worldwide mortality. Hence, this report describes a pDM4-based site-directed mutagenesis strategy that is assisting in our foremost objective to better understand the fundamental workings of the T3SS, using Yersinia as a model pathogenic bacterium. Examples are given that clearly document how pDM4-mediated site-directed mutagenesis has been used to establish clean point mutations and in-frame deletion mutations that have been instrumental in identifying and understanding the molecular interactions between components of the Yersinia type III secretion system.

  • 196.
    Francis, Matthew S
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Auerbuch, Victoria
    Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, Santa Cruz, CA, United States.
    Editorial: The Pathogenic Yersiniae–Advances in the Understanding of Physiology and Virulence, Second Edition2019Inngår i: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, s. 1-5, artikkel-id 119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Of the 18 known Yersinia species, Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica are pathogenic to humans and animals and are widely characterized. The zoonotic obligate pathogen Y. pestis is the causal agent of plague, a systemic disease that is usually fatal if left untreated (Zietz and Dunkelberg, 2004; Zhou et al., 2006). Free-living Y. enterocolitica and Y. pseudotuberculosis are the agents of yersiniosis, a rarely systemic gastrointestinal disease (Galindo et al., 2011). The remaining species are mostly harmless to humans, although Y. ruckeri is an enteric fish pathogen affecting mainly salmonids, while a few others display toxicity toward insects (Sulakvelidze, 2000; Tobback et al., 2007; Fuchs et al., 2008; Chen et al., 2010). At the forefront of Yersinia research are studies of classical microbiology, pathogenesis, protein secretion, niche adaptation, and regulation of gene expression. In pursuit of these endeavors, new frontiers are being forged on waves of methodological and technological innovation. In this second edition of the special research topic on the pathogenic Yersiniae is a compilation of reviews and research articles that summarize current knowledge and future research directions in the Yersinia pathophysiology field.

    Fulltekst (pdf)
    fulltext
  • 197.
    Francis, Matthew S
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinsk fakultet, Umeå Centre for Microbial Research (UCMR).
    Schesser, Kurt
    Forsberg, Åke
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Type III secretion systems in animal- and plant-interacting bacteria2004Inngår i: Cellular Microbiology, ASM Press, Washington, D.C. , 2004, s. 362-392Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
  • 198.
    Francis, Matthew
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Schesser, Kurt
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Forsberg, Åke
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Wolf-Watz, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Type III secretion systems in animal- and plant-interacting bacteria2000Inngår i: Cellular Microbiology, Washington, DC: ASM Press , 2000, 1, s. 239-263Kapittel i bok, del av antologi (Fagfellevurdert)
  • 199.
    Freire, Rafael V.M.
    et al.
    Department of Chemistry, University of Fribourg, Chemin Du Musée 9, 1700 Fribourg, Switzerland.
    Pillco-Valencia, Yeny
    Department of Fundamental Chemistry, Federal University of Pernambuco, Cidade Universitária, 50740-560 Recife, Brazil.
    da Hora, Gabriel C.A.
    Department of Fundamental Chemistry, Federal University of Pernambuco, Cidade Universitária, 50740-560 Recife, Brazil.
    Ramstedt, Madeleine
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sandblad, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Soares, Thereza A.
    Department of Fundamental Chemistry, Federal University of Pernambuco, Cidade Universitária, 50740-560 Recife, Brazil.
    Salentinig, Stefan
    epartment of Chemistry, University of Fribourg, Chemin Du Musée 9, 1700 Fribourg, Switzerland.
    Antimicrobial peptide induced colloidal transformations in bacteria-mimetic vesicles: combining in silico tools and experimental methods2021Inngår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 596, s. 352-363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With the growing challenges of bacteria becoming resistant to conventional antibiotics, antimicrobial peptides (AMPs) may offer a potential alternative. One of the most studied AMPs, the human cathelicidin derived AMP LL-37 is notable for its antimicrobial activity even though its mechanism of action is not fully understood yet. This work investigates the interaction of LL-37 with 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (POPG) vesicles, which were employed as a bacterial membrane model given the common presence of this phospholipid in the bacterial membrane. Experimental techniques including small angle X-ray scattering, transmission electron microscopy and dynamic light scattering were used to characterize the interactions among LL-37 and POPG. Molecular dynamics simulations complement the experimental studies with molecular-level insights into the process. LL-37 was discovered to actively and critically interact with the POPG vesicles, modifying the membrane curvature that eventually leads to structural transformations from vesicles to mixed micelles. The results shed light on the mechanisms underlying the interactions among LL-37 and bacteria mimetic vesicles and can guide the further development of AMP based antimicrobial materials and therapies.

    Fulltekst (pdf)
    fulltext
  • 200.
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Co- and polymicrobial infections in the gut mucosa: the host-microbiota-pathogen perspective2021Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 23, nr 2, artikkel-id e13279Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Infections in humans occur in the context of complex niches where the pathogen interacts with both the host microenvironment and immune response, and the symbiotic microbial community. The polymicrobial nature of many human infections adds a further layer of complexity. The effect of co- or polymicrobial infections can result in enhanced severity due to pathogens cooperative interaction or reduced morbidity because one of the pathogens affects the fitness of the other(s). In this review, the concept of co-infections and polymicrobial interactions in the context of the intestinal mucosa is discussed, focusing on the interplay between the host, the microbiota and the pathogenic organisms. Specifically, we will examine examples of pathogen-cooperative versus -antagonistic behaviour during co- and polymicrobial infections. We discuss: the infection-induced modulation of the host microenvironment and immune responses; the direct modulation of the microorganism's fitness; the potentiation of inflammatory/carcinogenic conditions by polymicrobial biofilms; and the promotion of co-infections by microbial-induced DNA damage. Open questions in this very exciting field are also highlighted.

    Fulltekst (pdf)
    fulltext
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