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  • 101. Felgner, S
    et al.
    Frahm, M
    Kocijancic, D
    Rohde, M
    Eckweiler, D
    Bielecka, A
    Bueno, Emilio
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Abraham, WR
    Curtiss, R
    Häussler, S
    Erhardt, M
    Weiss, S
    aroA-Deficient Salmonella enterica Serovar Typhimurium Is More Than a Metabolically Attenuated Mutant2016In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, no 5, article id e01220-16Article in journal (Refereed)
    Abstract [en]

    Recombinant attenuated Salmonella enterica serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of aroA, are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of aroA dramatically increased the virulence of attenuated Salmonella in mouse models. Mutant bacteria lacking aroA elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) after systemic application. A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that Delta aroA mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of aroA affected flagellin phase variation and gene expression of the virulence-associated genes arnT and ansB. Finally, Delta aroA strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of Delta aroA-attenuated Salmonella for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine. 

    IMPORTANCE Recombinant attenuated bacterial vector systems based on genetically engineered Salmonella have been developed as highly potent vaccines. Due to the pathogenic properties of Salmonella, efficient attenuation is required for clinical applications. Since the hallmark study by Hoiseth and Stocker in 1981 (S. K. Hoiseth and B. A. D. Stocker, Nature 291:238-239, 1981, http://dx.doi.org/10.1038/291238a0), the auxotrophic Delta aroA mutation has been generally considered safe and universally used to attenuate bacterial strains. Here, we are presenting the remarkable finding that a deletion of aroA leads to pronounced alterations of gene expression, metabolism, and cellular physiology, which resulted in increased immunogenicity, virulence, and adjuvant potential of Salmonella. These results suggest that the enhanced immunogenicity of aroA-deficient Salmonella strains might be advantageous for optimizing bacterial vaccine carriers and immunotherapy. Accordingly, we demonstrate a superior performance of Delta aroA Salmonella in bacterium-mediated tumor therapy. In addition, the present study highlights the importance of a functional shikimate pathway to sustain bacterial physiology and metabolism.

  • 102.
    Ferro, Lorenza
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wastewater treatment and biomass generation by Nordic microalgae: growth in subarctic climate and microbial interactions2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nordic native microalgal strains were isolated, genetically classified and tested for their ability to grow in municipal wastewater. Eight of the isolated strains could efficiently remove nitrogen and phosphate in less than two weeks. Two of these strains, Coelastrella sp. and Chlorella vulgaris, were found to have high biomass concentration and total lipid content; also two Desmodesmus sp. strains showed desirable traits for biofuel-feedstock, due to their fast growth rates and high oil content.

    The adaptation to subarctic climate was comparatively evaluated in three Nordic strains (C. vulgaris, Scenedesmus sp. and Desmodesmus sp.) and a collection strain (S. obliquus). Their growth performance, biomass composition and nutrients removal was investigated at standard (25°C) or low temperature (5°C), under continuous light at short photoperiod (3 h light, 25°C) or moderate winter conditions (6 h light, 15°C). Only the Nordic strains could grow and produce biomass at low temperature, and efficiently removed nitrogen and phosphate during both cold- and dark-stress. Phenotypic plasticity was observed in Scenedesmus and Desmodesmus under different growth conditions, adaptation to low temperature increased their carbohydrate content. Short photoperiod strongly reduced growth rates, biomass and storage compounds in all strains and induced flocculation in C. vulgaris, which, however, performed best under moderate winter conditions.

    The symbiotic relationships between the Nordic microalga C. vulgaris and the naturally co-occurring bacterium Rhizobium sp. were investigated batchwise under photoautotrophic, heterotrophic and mixotrophic conditions, comparing the co-culture to the axenic cultures. The photoautotrophic algal growth in BG11 medium mainly supported Rhizobium activity in the co-culture, with no significant effects on C. vulgaris. In synthetic wastewater, a synergistic interaction only occurred under mixotrophic conditions, supported by CO2/O2 exchange and a lower pH in the culture, resulting in higher biomass and fatty acids content and more efficient wastewater treatment in the co-culture. Under heterotrophic conditions, the lower biomass production in the co-culture suggested a competition for nutrients, although nutrients removal remained efficient.

    A pilot-scale high rate algal pond (HRAP) located in Northern Sweden was inoculated with the collection strain Scenedesmus dimorphus UTEX 417 and operated from spring to autumn. Using metabarcoding of 18S and 16S rRNA genes, the microbial diversity of eukaryotic and prokaryotic communities was revealed. S. dimorphus was initially stable in the culture, but other microalgal species later colonized the system, mainly due to parasitic infections and predation by zooplankton in summer. The main competitor algal species were Desmodesmus, Pseudocharaciopsis, Chlorella, Characium and Oocystis. Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria were the most abundant bacterial phyla in the HRAP. The structure of the microbial communities followed a seasonal variation and partially correlated to environmental factors such as light, temperature and nutrients concentrations.

    Overall, these results contribute with new knowledge on the establishment and optimization of microalgal-based wastewater treatment systems coupled with biomass generation in Nordic areas. The use of native microalgal species is proposed as a potential strategy to overcome the limitations posed to algal cultivation in subarctic regions.

  • 103.
    Ferro, Lorenza
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemical Engineering and Environmental Technology, School of Industrial Engineering, University of Valladolid, Valladolid, Spain.
    Colombo, Michela
    Posadas, Esther
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Muñoz, Raul
    Elucidating the symbiotic interactions between a locally isolated microalga Chlorella vulgaris and its co-occurring bacterium Rhizobium sp. in synthetic municipal wastewater2019In: Journal of Applied Phycology, ISSN 0921-8971, E-ISSN 1573-5176, Vol. 31, no 4, p. 2299-2310Article in journal (Refereed)
    Abstract [en]

    Co-cultivation of microalgae and bacteria during municipal wastewater treatment can boost carbon and nutrient recovery as a result of their synergistic interactions. The symbiotic relationships between the locally isolated microalga Chlorella vulgaris and the bacterium Rhizobium sp., co-isolated from municipal wastewater, were investigated batchwise under photoautotrophic, heterotrophic, and mixotrophic conditions in a synthetic municipal wastewater medium. During photoautotrophic growth in BG11 medium, photosynthetic algal oxygenation and organic carbon production supported bacterial activity but no significant beneficial effects on microalgal growth were observed. In synthetic wastewater, a twofold higher biomass concentration was achieved in the axenic algal culture compared with the co-culture under heterotrophic conditions, suggesting a competition for nutrients. A comparable carbon removal was observed in all cultures (83–79% TOC), but a faster nitrogen consumption (59% TN) and complete phosphate assimilation (100% TP) was only achieved in the co-culture. A positive synergistic relationship was found under mixotrophic conditions, clearly supported by an in situ O2/CO2 exchange between the microorganisms. This mutualism led to a threefold higher biomass production with a 13-fold higher fatty acid content compared with the axenic algal culture, as well as a superior wastewater treatment performance (+ 58% TOC, + 41% TN and + 44% TP). The co-cultivation of C. vulgaris and Rhizobium is therefore suggested as a potential microbial consortium for a cost-efficient biomass generation during municipal wastewater reclamation, especially under mixotrophic conditions.

  • 104.
    Ferro, Lorenza
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gorzsás, András
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gentili, Francesco G.
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Subarctic microalgal strains treat wastewater and produce biomass at low temperature and short photoperiod2018In: Algal Research, ISSN 2211-9264, Vol. 35, p. 160-167Article in journal (Refereed)
    Abstract [en]

    In Northern countries, microalgal-based processes are challenging due to low light and temperature conditions during a significant part of the year. Three natural strains from Northern Sweden (Chlorella vulgaris, Scenedesmus sp., Desmodesmus sp.) and a collection strain (Scenedesmus obliquus UTEX 417) were cultured in municipal wastewater, comparing their performances, biomass composition and nutrients removal under continuous light at standard (25 °C) and low temperature (5 °C), short photoperiod (3 h light, 25 °C), or moderate winter conditions (6 h light, 15 °C). Only the natural strains grew at low temperature, highly consuming total nitrogen and phosphate (>80% and >70%, respectively) even during cold- and dark-stress. At reduced growth rates, C. vulgaris and Scenedesmus sp. produced similar amounts of biomass (>1 g/l) as in standard conditions. Scenedesmus sp. and Desmodesmus sp. showed phenotypic plasticity and increased carbohydrate content. Short photoperiod strongly reduced growth rates, biomass and storage compounds and induced flocculation in C. vulgaris.

  • 105.
    Ferro, Lorenza
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hu, Yue
    Gentili, Francesco
    Andersson, Anders
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Microbial population dynamics in a microalgae-based municipal wastewater treatment photobioreactor located in Northern SwedenManuscript (preprint) (Other academic)
    Abstract [en]

    A pilot-scale high-rate algal pond (HRAP) located in Northern Sweden was inoculated with the collection strain S. dimorphus UTEX 417 in spring and operated until autumn. The microbial diversity of eukaryotic and prokaryotic communities and their seasonal dynamics over time were revealed by high-throughput metabarcoding of 18S and 16S rRNA genes and correlated with various environmental factors. S. dimorphus was initially stable in the culture, but other microalgae appeared later and co-dominate the system as a consequence of predation by zooplankton. Desmodesmus, Pseudocharaciopsis, Chlorella, Characium and Oocystis were the main competing algal species. Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria were the most abundant bacterial phyla in the HRAP. The bacterial and zooplanktonic communities changed with seasonal variation, correlation not only with changes in light and temperature, but also with abiotic factors (pH and nutrients) were observed.

  • 106.
    Ferro, Lorenza
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Miranda, Fernanda
    Gentili, Francesco
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Photosynthesis at high latitudes: adaptation of photosynthetic microorganisms to Nordic climates2020In: Biotechnological Applications of Extremophilic Microorganisms / [ed] Lee, Natuschka M., Walter de Gruyter, 2020Chapter in book (Other academic)
  • 107. Forns, Núria
    et al.
    Baños, Rosa C
    Balsalobre, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Juárez, Antonio
    Madrid, Cristina
    Temperature-dependent conjugative transfer of R27: Role of chromosome- and plasmid-encoded Hha and H-NS proteins2005In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 187, no 12, p. 3950-3959Article in journal (Refereed)
    Abstract [en]

    IncHI plasmids encode multiple-antibiotic resistance in Salmonella enterica serovar Typhi. These plasmids have been considered to play a relevant role in the persistence and reemergence of this microorganism. The IncHII plasmid R27, which can be considered the prototype of IncHI plasmids, is thermosensitive for transfer. Conjugation frequency is highest at low temperature (25 to 30 degrees C), decreasing when temperature increases. R27 codifies an H-NS-like protein (open reading frame 164 [ORF164]) and an Hha-like protein (ORF182). The H-NS and Hha proteins participate in the thermoregulation of gene expression in Escherichia coli. Here we investigated the hypothetical role of such proteins in thermoregulation of R27 conjugation. At a nonpermissive temperature (33 degrees C), transcription of several ORFs in both transfer region I (Tra1) and Tra2 from R27 is upregulated in cells depleted of Hha-like and H-NS-like proteins. Both chromosome- and plasmid-encoded Hha and H-NS proteins appear to potentially modulate R27 transfer. The function of R27-encoded Hha-like and H-NS proteins is not restricted to modulation of R27 transfer. Different mutant phenotypes associated with both chromosomal hha and hns mutations are compensated in cells harboring R27.

  • 108.
    Francis, Matthew
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Secretion systems and metabolism in the pathogenic Yersiniae2011In: Stress response in pathogenic bacteria / [ed] Stephen P. Kidd, United Kingdom: CAB International , 2011, 1, p. 185-220Chapter in book (Refereed)
    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.

  • 109.
    Francis, Matthew
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    The pathogenic Yersiniae: advances in the understanding of physiology and virulence2013In: Frontiers in Cellular and Infection Microbiology, ISSN 2235-2988, Vol. 3, no 51, p. 2p. 1-2Article, review/survey (Refereed)
  • 110.
    Francis, Matthew S
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, 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 Edition2019In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, p. 1-5, article id 119Article in journal (Refereed)
    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.

  • 111.
    Frisan, Teresa
    Dept. Cell and Molecular Biology, Karolinska Institutet.
    Bacterial genotoxins: the long journey to the nucleus of mammalian cells2016In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1858, no 3, p. 567-575, article id S0005-2736(15)00267-9Article, review/survey (Refereed)
    Abstract [en]

    Bacterial protein genotoxins target the DNA of eukaryotic cells, causing DNA single and double strand breaks. The final outcome of the intoxication is induction of DNA damage responses and activation of DNA repair pathways. When the damage is beyond repair, the target cell either undergoes apoptosis or enters a permanent quiescent stage, known as cellular senescence. In certain instances, intoxicated cells can survive and proliferate. This event leads to accumulation of genomic instability and acquisition of malignant traits, underlining the carcinogenic potential of these toxins. The toxicity is dependent on the toxins' internalization and trafficking from the extracellular environment to the nucleus, and requires a complex interaction with several cellular membrane compartments: the plasma membrane, the endosomes, the trans Golgi network and the endoplasmic reticulum, and finally the nucleus. This review will discuss the current knowledge of the bacterial genotoxins internalization pathways and will highlight the issues that still remain unanswered. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

  • 112.
    Frisan, Teresa
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Coppotelli, Giuseppe
    Dryselius, Rikard
    Masucci, Maria G
    Ubiquitin C-terminal hydrolase-L1 interacts with adhesion complexes and promotes cell migration, survival, and anchorage independent growth2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 12, p. 5060-5070Article in journal (Refereed)
    Abstract [en]

    Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a deubiquitinating enzyme of unknown function that is highly expressed in neurons and overexpressed in several human cancers. UCH-L1 has been implicated in the regulation of phenotypic properties associated with malignant cell growth but the underlying mechanisms have not been elucidated. By comparing cells expressing catalytically active or inactive versions of UCH-L1, we found that the active enzyme enhances cell adhesion, spreading, and migration; inhibits anoikis; and promotes anchorage independent growth. UCH-L1 accumulates at the motile edge of the cell membrane during the initial phases of adhesion, colocalizes with focal adhesion kinase (FAK), p120-catenin, and vinculin, and enhances the formation of focal adhesions, which correlates with enhanced FAK activation. The involvement of UCH-L1 in the regulation of focal adhesions and adherens junctions is supported by coimmunoprecipitation with key components of these complexes, including FAK, paxillin, p120-catenin, β-catenin, and vinculin. UCH-L1 stabilizes focal adhesion signaling in the absence of adhesion, as assessed by reduced caspase-dependent cleavage of FAK following cell detachment and sustained activity of the AKT signaling pathway. These findings offer new insights on the molecular interactions through which the deubiquitinating enzyme regulates the survival, proliferation, and metastatic potential of malignant cells.

  • 113.
    Frisan, Teresa
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Sebo, Peter
    Editorial: Why still study bacterial toxins in the third millennium?2016In: Pathogens and Disease, E-ISSN 2049-632X, Vol. 74, no 3, article id ftw009Article in journal (Refereed)
  • 114.
    Frithz-Lindsten, Elisabet
    et al.
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Holmström, Anna
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Jacobsson, Lars
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Soltani, Mehnam
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Olsson, Jan
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    Department of Microbiology, Defence Research Establishment, S-901 82, Umeå, Sweden.
    Functional conservation of the effector protein translocators PopB/YopB and PopD/YopD of Pseudomonas aeruginosa and Yersinia pseudotuberculosis.1998In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 29, no 5, p. 1155-1165Article in journal (Refereed)
    Abstract [en]

    Virulent Yersinia species cause systemic infections in rodents, and Y. pestis is highly pathogenic for humans. Pseudomonas aeruginosa, on the other hand, is an opportunistic pathogen, which normally infects only compromised individuals. Surprisingly, these pathogens both encode highly related contact-dependent secretion systems for the targeting of toxins into eukaryotic cells. In Yersinia, YopB and YopD direct the translocation of the secreted Yop effectors across the target cell membrane. In this study, we have analysed the function of the YopB and YopD homologues, PopB and PopD, encoded by P. aeruginosa. Expression of the pcrGVHpopBD operon in defined translocation-deficient mutants (yopB/yopD) of Yersinia resulted in complete complementation of the cell contact-dependent, YopE-induced cytotoxicity of Y. pseudotuberculosis on HeLa cells. We demonstrated that the complementation fully restored the ability of Y. pseudotuberculosis to translocate the effector molecules YopE and YopH into the HeLa cells. Similar to YopB, PopB induced a lytic effect on infected erythrocytes. The lytic activity induced by PopB could be prevented if the erythrocytes were infected in the presence of sugars larger than 3 nm in diameter, indicating that PopB induced a pore of similar size compared with that induced by YopB. Our findings show that the contact-dependent toxin-targeting mechanisms of Y. pseudotuberculosis and P. aeruginosa are conserved at the molecular level and that the translocator proteins are functionally interchangeable. Based on these similarities, we suggest that the translocation of toxins such as ExoS, ExoT and ExoU by P. aeruginosa across the eukaryotic cell membrane occurs via a pore induced by PopB.

  • 115. Genisset, Christophe
    et al.
    Puhar, Andrea
    Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, Padova, Italy..
    Calore, Federica
    de Bernard, Marina
    Dell'Antone, Paolo
    Montecucco, Cesare
    The concerted action of the Helicobacter pylori cytotoxin VacA and of the v-ATPase proton pump induces swelling of isolated endosomes2007In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 9, no 6, p. 1481-1490Article in journal (Refereed)
    Abstract [en]

    The vacuolating cytotoxin (VacA) is a major virulence factor of Helicobacter pylori, the bacterium associated to gastroduodenal ulcers and stomach cancers. VacA induces formation of cellular vacuoles that originate from late endosomal compartments. VacA forms an anion-selective channel and its activity has been suggested to increase the osmotic pressure in the lumen of these acidic compartments, driving their swelling to vacuoles. Here, we have tested this proposal on isolated endosomes that allow one to manipulate at will the medium. We have found that VacA enhances the v-ATPase proton pump activity and the acidification of isolated endosomes in a Cl- dependent manner. Other counter-anions such as pyruvate, Br-, I- and SCN- can be transported by VacA with stimulation of the v-ATPase. The VacA action on isolated endosomes is associated with their increase in size. Single amino acid substituted VacA with no channel-forming and vacuolating activity is unable to induce swelling of endosomes. These data provide a direct evidence that the transmembrane VacA channel mediates an influx of anions into endosomes that stimulates the electrogenic v-ATPase proton pump, leading to their osmotic swelling and transformation into vacuoles.

  • 116. Goormaghtigh, Frederic
    et al.
    Fraikin, Nathan
    Putrins, Marta
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu, Estonia.
    Garcia-Pino, Abel
    Udekwu, Klas
    Tenson, Tanel
    Kaldalu, Niilo
    Van Melderen, Laurence
    Reply to Holden and Errington, "Type II Toxin-Antitoxin Systems and Persister Cells"2018In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 5, article id e01838-18Article in journal (Refereed)
  • 117. Grasso, Francesca
    et al.
    Frisan, Teresa
    Department Cell and Molecular Biology, Karolinska Institutet.
    Bacterial Genotoxins: Merging the DNA Damage Response into Infection Biology2015In: Biomolecules, E-ISSN 2218-273X, Vol. 5, no 3, p. 1762-1782Article, review/survey (Refereed)
    Abstract [en]

    Bacterial genotoxins are unique among bacterial toxins as their molecular target is DNA. The consequence of intoxication or infection is induction of DNA breaks that, if not properly repaired, results in irreversible cell cycle arrest (senescence) or death of the target cells. At present, only three bacterial genotoxins have been identified. Two are protein toxins: the cytolethal distending toxin (CDT) family produced by a number of Gram-negative bacteria and the typhoid toxin produced by Salmonella enterica serovar Typhi. The third member, colibactin, is a peptide-polyketide genotoxin, produced by strains belonging to the phylogenetic group B2 of Escherichia coli. This review will present the cellular effects of acute and chronic intoxication or infection with the genotoxins-producing bacteria. The carcinogenic properties and the role of these effectors in the context of the host-microbe interaction will be discussed. We will further highlight the open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.

  • 118. Griffin, Robert M.
    et al.
    Dean, Rebecca
    Grace, Jaime L.
    Ryden, Patrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Friberg, Urban
    The Shared Genome Is a Pervasive Constraint on the Evolution of Sex-Biased Gene Expression2013In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 30, no 9, p. 2168-2176Article in journal (Refereed)
    Abstract [en]

    Males and females share most of their genomes, and differences between the sexes can therefore not evolve through sequence divergence in protein coding genes. Sexual dimorphism is instead restricted to occur through sex-specific expression and splicing of gene products. Evolution of sexual dimorphism through these mechanisms should, however, also be constrained when the sexes share the genetic architecture for regulation of gene expression. Despite these obstacles, sexual dimorphism is prevalent in the animal kingdom and commonly evolves rapidly. Here, we ask whether the genetic architecture of gene expression is plastic and easily molded by sex-specific selection, or if sexual dimorphism evolves rapidly despite pervasive genetic constraint. To address this question, we explore the relationship between the intersexual genetic correlation for gene expression (r(MF)), which captures how independently genes are regulated in the sexes, and the evolution of sex-biased gene expression. Using transcriptome data from Drosophila melanogaster, we find that most genes have a high r(MF) and that genes currently exposed to sexually antagonistic selection have a higher average r(MF) than other genes. We further show that genes with a high r(MF) have less pronounced sex-biased gene expression than genes with a low r(MF) within D. melanogaster and that the strength of the r(MF) in D. melanogaster predicts the degree to which the sex bias of a gene's expression has changed between D. melanogaster and six other species in the Drosophila genus. In sum, our results show that a shared genome constrains both short- and long-term evolution of sexual dimorphism.

  • 119.
    Gripenland, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Christopher
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Evaluating the chicken embryo as a model for studying Listeria monocytogenes pathogenesis: a role for the PrfA pathwayManuscript (preprint) (Other academic)
  • 120. Guerra, Lina
    et al.
    Cortes-Bratti, Ximena
    Guidi, Riccardo
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    The biology of the cytolethal distending toxins2011In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 3, no 3, p. 172-190Article, review/survey (Refereed)
    Abstract [en]

    The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B(2) toxin, where the CdtA and CdtC subunits are required to mediate the binding on the surface of the target cells, allowing internalization of the active CdtB subunit, which is functionally homologous to the mammalian deoxyribonuclease I. The nature of the surface receptor is still poorly characterized, however binding of CDT requires intact lipid rafts, and its internalization occurs via dynamin-dependent endocytosis. The toxin is retrograde transported through the Golgi complex and the endoplasmic reticulum, and subsequently translocated into the nuclear compartment, where it exerts the toxic activity. Cellular intoxication induces DNA damage and activation of the DNA damage responses, which results in arrest of the target cells in the G1 and/or G2 phases of the cell cycle and activation of DNA repair mechanisms. Cells that fail to repair the damage will senesce or undergo apoptosis. This review will focus on the well-characterized aspects of the CDT biology and discuss the questions that still remain unanswered.

  • 121. Guerra, Lina
    et al.
    Guidi, Riccardo
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression?2011In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 278, no 23, p. 4577-4588Article, review/survey (Refereed)
    Abstract [en]

    Cytolethal distending toxin, produced by several Gram-negative bacteria, and colibactin, secreted by several commensal and extraintestinal pathogenic Escherichia coli strains, are the first bacterial genotoxins to be described to date. Exposure to cytolethal distending toxin and colibactin induces DNA damage, and consequently activates the DNA damage response, resulting in cell cycle arrest of the intoxicated cells and DNA repair. Irreversible DNA damage will lead to cell death by apoptosis or to senescence. It is well established that chronic exposure to DNA damaging agents, either endogenous (reactive oxygen species) or exogenous (ionizing radiation), may cause genomic instability as a result of the alteration of genes coordinating the DNA damage response, thus favoring tumor initiation and progression. In this review, we summarize the state of the art of the biology of cytolethal distending toxin and colibactin, focusing on the activation of the DNA damage response and repair pathways, and discuss the cellular responses induced in intoxicated cells, as well as how prolonged intoxication may lead to chronic inflammation, the accumulation of genomic instability, and tumor progression in both in vitro and in vivo models.

  • 122. Guerra, Lina
    et al.
    Guidi, Riccardo
    Slot, Ilse
    Callegari, Simone
    Sompallae, Ramakrishna
    Pickett, Carol L
    Åström, Stefan
    Eisele, Frederik
    Wolf, Dieter
    Sjögren, Camilla
    Masucci, Maria G
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm.
    Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival2011In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 16, p. 2735-2742Article in journal (Refereed)
    Abstract [en]

    The DNA damage response triggered by bacterial cytolethal distending toxins (CDTs) is associated with activation of the actin-regulating protein RhoA and phosphorylation of the downstream-regulated mitogen-activated protein kinase (MAPK) p38, which promotes the survival of intoxicated (i.e. cells exposed to a bacterial toxin) cells. To identify the effectors of this CDT-induced survival response, we screened a library of 4492 Saccharomyces cerevisiae mutants that carry deletions in nonessential genes for reduced growth following inducible expression of CdtB. We identified 78 genes whose deletion confers hypersensitivity to toxin. Bioinformatics analysis revealed that DNA repair and endocytosis were the two most overrepresented signaling pathways. Among the human orthologs present in our data set, FEN1 and TSG101 regulate DNA repair and endocytosis, respectively, and also share common interacting partners with RhoA. We further demonstrate that FEN1, but not TSG101, regulates cell survival, MAPK p38 phosphorylation, RhoA activation and actin cytoskeleton reorganization in response to DNA damage. Our data reveal a previously unrecognized crosstalk between DNA damage and cytoskeleton dynamics in the regulation of cell survival, and might provide new insights on the role of chronic bacteria infection in carcinogenesis.

  • 123. Guidi, R
    et al.
    Belluz, L Del Bell
    Frisan, Teresa
    Dept. of Cell and Molecular Biology, Karolinska Institute, Stockholm Sweden.
    Bacterial genotoxin functions as immune-modulator and promotes host survival2016In: Microbial cell (Graz, Austria), ISSN 2311-2638, Vol. 3, no 8, p. 355-357Article in journal (Refereed)
    Abstract [en]

    Bacterial genotoxins are effectors that cause DNA damage in target cells. Many aspects of the biology of these toxins have been characterised in vitro, such as structure, cellular internalisation pathways and effects on the target cells. However, little is known about their function in vivo. Salmonella enterica serovar Typhi (S. Typhi) is a Gram-negative, intracellular bacterium that causes typhoid fever, a debilitating disease infecting more than 20 million people every year. S. Typhiproduce a genotoxin named typhoid toxin (TT), but its role in the contest of host infection is poorly characterized. The major obstacle in addressing this issue is that S. Typhi is exclusively a human pathogen. To overcome this limitation, we have used as model bacterium S. Typhimurium, and engineered it to produce endogenous levels of an active and inactive typhoid toxin, hereby named as TT (or genotoxic) and cdtB (or control), respectively. To our surprise, infection with the genotoxin strain strongly suppressed intestinal inflammation, leading to a better survival of the host during the acute phase of infection, suggesting typhoid toxin may exert a protective role. The presence of a functional genotoxin was also associated with an increased frequency of asymptomatic carriers.

  • 124. Guidi, Riccardo
    et al.
    Guerra, Lina
    Levi, Laura
    Stenerlöw, Bo
    Fox, James G
    Josenhans, Christine
    Masucci, Maria G
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response2013In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 1, p. 98-113Article in journal (Refereed)
    Abstract [en]

    Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process.

  • 125. Guidi, Riccardo
    et al.
    Levi, Laura
    Rouf, Syed Fazle
    Puiac, Speranta
    Rhen, Mikael
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden..
    Salmonella enterica delivers its genotoxin through outer membrane vesicles secreted from infected cells2013In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 12, p. 2034-2050Article in journal (Refereed)
    Abstract [en]

    Cytolethal-distending toxins (CDTs) belong to a family of DNA damage inducing exotoxins that are produced by several Gram-negative bacteria. Salmonella enterica serovar Typhi expresses its CDT (named as Typhoid toxin) only in the Salmonella-containing vacuole (SCV) of infected cells, which requires its export for cell intoxication. The mechanisms of secretion, release in the extracellular space and uptake by bystander cells are poorly understood. We have addressed these issues using a recombinant S. Typhimurium strain, MC71-CDT, where the genes encoding for the PltA, PltB and CdtB subunits of the Typhoid toxin are expressed under control of the endogenous promoters. MC71-CDT grown under conditions that mimic the SCV secreted the holotoxin in outer membrane vesicles (OMVs). Epithelial cells infected with MC71-CDT also secreted OMVs-like vesicles. The release of these extracellular vesicles required an intact SCV and relied on anterograde transport towards the cellular cortex on microtubule and actin tracks. Paracrine internalization of Typhoid toxin-loaded OMVs by bystander cells was dependent on dynamin-1, indicating active endocytosis. The subsequent induction of DNA damage required retrograde transport of the toxin through the Golgi complex. These data provide new insights on the mode of secretion of exotoxins by cells infected with intracellular bacteria.

  • 126.
    Gurung, Jyoti M.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Amer, Ayad
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Francis, Monika
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Costa, Tiago
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chen, Shiyun
    Zavialov, Anton V.
    Francis, Matthew S.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Heterologous complementation studies with the YscX and YscY protein families reveals a specificity for Yersinia pseudotuberculosis type III secretion2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 80Article in journal (Refereed)
    Abstract [en]

    Type III secretion systems harbored by several Gram-negative bacteria are often used to deliver host-modulating effectors into infected eukaryotic cells. About 20 core proteins are needed for assembly of a secretion apparatus. Several of these proteins are genetically and functionally conserved in type III secretion systems of bacteria associated with invertebrate or vertebrate hosts. In the Ysc family of type III secretion systems are two poorly characterized protein families, the YscX family and the YscY family. In the plasmid-encoded Ysc-Yop type III secretion system of human pathogenic Yersinia species, YscX is a secreted substrate while YscY is its non-secreted cognate chaperone. Critically, neither an yscX nor yscY null mutant of Yersinia is capable of type III secretion. In this study, we show that the genetic equivalents of these proteins produced as components of other type III secretion systems of Pseudomonas aeruginosa (PscX and PscY), Aeromonas species (AscX and AscY), Vibrio species (VscX and VscY), and Photorhabdus luminescens (SctX and SctY) all possess an ability to interact with its native cognate partner and also establish cross-reciprocal binding to non-cognate partners as judged by a yeast two-hybrid assay. Moreover, a yeast three-hybrid assay also revealed that these heterodimeric complexes could maintain an interaction with YscV family members, a core membrane component of all type III secretion systems. Despite maintaining these molecular interactions, only expression of the native yscX in the near full-length yscX deletion and native yscY in the near full-length yscY deletion were able to complement for their general substrate secretion defects. Hence, YscX and YscY must have co-evolved to confer an important function specifically critical for Yersinia type III secretion.

  • 127.
    Gustafsson, Dan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus species B interactions with CD462012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adenoviruses (Ad) are double-stranded (ds) DNA, non-enveloped viruses. There are seven species (A-G) of human Ads with 52 knownserotypes to date. Human Ads cause a broad range of pathologies, ranging from upper respiratory tract infections to persistent urinary tract infections. The main determinant for Ads tropism in vitro is the protruding, antenna-like, fiber protein. The fiberknob is responsible for the main interaction with the attachment receptor of the host cell. Most Ad species use the coxsackie- adenovirus receptor (CAR) as their main attachment receptor. Most species B Ads, however use CD46. CD46 is a cell surface complement regulatory protein, which is expressed on all nucleated cells in humans. Species B Ads exhibit a low seroprevalenc in the human population, making these Ads promising vector candidates for gene therapy. We have studied human Ad species B members, serotypes 7 and 11 (Ad7 and Ad11), as well as their interaction with CD46. Our first experiments showed that all species B Ads use CD46 as their main attachment receptor, with the exception of Ad3 and Ad7. Second, we performed mutational studies of recombinant Ad11p fiberknobs. These studies showed that arginine 279 in the Ad 11 fiberknob is necessary for CD46 binding. Finally we studied the effect of Ad11 binding to CD46. The results indicate that CD46 is rapidly downregulated on the cell surface after Ad11 binding. These results may provide a further understanding of the basic biology and pathology of species B Ads and may also be useful in construction of gene therapy vectors based on species B Ads.

  • 128.
    Gómez-Consarnau, Laura
    et al.
    Linnéuniversitetet, Institutionen för naturvetenskap, NV.
    Lindh, Markus V.
    Linnéuniversitetet, Institutionen för naturvetenskap, NV.
    Gasol, Josep M.
    Pinhassi, Jarone
    Linnéuniversitetet, Institutionen för naturvetenskap, NV.
    Structuring of bacterioplankton communities by specific dissolved organic carbon compounds2012In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 14, no 9, p. 2361-2378Article in journal (Refereed)
    Abstract [en]

    The main role of microorganisms in the cycling of the bulk dissolved organic carbon pool in the ocean is well established. Nevertheless, it remains unclear if particular bacteria preferentially utilize specific carbon compounds and whether such compounds have the potential to shape bacterial community composition. Enrichment experiments in the Mediterranean Sea, Baltic Sea and the North Sea (Skagerrak) showed that different low-molecular-weight organic compounds, with a proven importance for the growth of marine bacteria (e.g. amino acids, glucose, dimethylsulphoniopropionate, acetate or pyruvate), in most cases differentially stimulated bacterial growth. Denaturing gradient gel electrophoresis fingerprints and 16S rRNA gene sequencing revealed that some bacterial phylotypes that became abundant were highly specific to enrichment with specific carbon compounds (e.g. Acinetobacter sp. B1-A3 with acetate or Psychromonas sp. B3-U1 with glucose). In contrast, other phylotypes increased in relative abundance in response to enrichment with several, or all, of the investigated carbon compounds (e.g. Neptuniibacter sp. M2-A4 with acetate, pyruvate and dimethylsulphoniopropionate, and Thalassobacter sp. M3-A3 with pyruvate and amino acids). Furthermore, different carbon compounds triggered the development of unique combinations of dominant phylotypes in several of the experiments. These results suggest that bacteria differ substantially in their abilities to utilize specific carbon compounds, with some bacteria being specialists and others having a more generalist strategy. Thus, changes in the supply or composition of the dissolved organic carbon pool can act as selective forces structuring bacterioplankton communities.

  • 129.
    Hagström, Åke
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Azam, Farooq
    Andersson, Agneta
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wikner, Johan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Raassoulzadegan, Fereidoun
    Microbial loop in an oligothropic pelagic marine ecosystem: Possible roles of cyanobacteria and nanoflagellates in the organic fluxes1988In: Marine Ecology Progress Series, ISSN 0171-8630, E-ISSN 1616-1599, Vol. 49, no 1-2, p. 171-178Article in journal (Refereed)
  • 130.
    Hammarström, Sten
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Is there a role for CEA in innate immunity in the colon?2001In: Trends in Microbiology, ISSN 0966-842X, E-ISSN 1878-4380, Vol. 9, no 3, p. 119-25Article in journal (Refereed)
    Abstract [en]

    Carcinoembryonic antigen (CEA) is a well known tumor marker associated with the progression of colorectal tumors. The CEA family of glycoproteins has been fully characterized and the function of some of its members is now beginning to be understood. Here, we advance the hypothesis that, rather than functioning in cell adhesion as has been suggested previously, CEA plays a role in protecting the colonic mucosa from microbial invasion. This hypothesis is based on new microscopic, molecular, phylogenetic and microbiological evidence.

  • 131.
    Hedberg, Maria E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Moore, Edward RB
    Svensson-Stadler, Liselott
    Hörstedt, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lachnoanaerobaculum a new genus in Lachnospiraceae; characterization of Lachnoanaerobaculum umeaense gen. nov., sp. nov., isolated from human small intestine, Lachnoanaerobaculum orale gen. nov., sp. nov., isolated from saliva and reclassification of Eubacterium saburreum (Prevot) Holdeman and Moore 1970 as Lachnoanaerobaculum saburreum comb. nov.2012In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 62, no 11, p. 2685-2690Article in journal (Refereed)
    Abstract [en]

    Two new obligately anaerobic Gram-positive, saccharolytic and non-proteolytic spore-forming bacilli (strain CD3:22 and N1) are described. Strain CD3:22 was isolated from a biopsy of the small intestine of a child with celiac disease and strain N1 from the saliva of a healthy young man. The cells of both strains were observed to be filamentous with lengths of approximately 5 to >20 µm, some of them curving and with swellings. The novel organisms produced H2S, NH3, butyric acid and acetic acid as major metabolic end products. Phylogenetic analyses, based on comparative 16S rRNA gene sequencing, revealed close relationships (98 % sequence similarity) between the two isolates, as well as the type strain of Eubacterium saburreum CCUG 28089T and four other Lachnospiraceae bacterium/E. saburreum-like organisms. This group of bacteria were clearly different from any of the 19 known genera in the family Lachnospiraceae. While Eubacterium spp. are reported to be non-spore-forming, reanalysis of E. saburreum CCUG 28089T confirmed that the bacterium, indeed, is able to form spores. Based on 16S rRNA gene sequencing, phenotypic and biochemical properties, CD3:22 (CCUG 58757T) and N1 (CCUG 60305T) represent new species of a new and distinct genus, named Lachnoanaerobaculum, in the family Lachnospiraceae [within the order Clostridiales, class Clostridia, phylum Firmicutes]. Strain CD3:22 is the type strain of the type species, Lachnoanaerobaculum umeaense gen. nov., sp. nov., of the proposed new genus. Strain N1 is the type strain of the species, Lachnoanaerobaculum orale gen. nov., sp. nov. Moreover, E. saburreum CCUG 28089T is reclassified as Lachnoanaerobaculum saburreum comb. nov.

  • 132. Hein, Kyaw Zaw
    et al.
    Takahashi, Hitoshi
    Tsumori, Toshiko
    Yasui, Yukihiko
    Nanjoh, Yasuko
    Toga, Tetsuo
    Wu, Zhihong
    Grötzinger, Joachim
    Jung, Sascha
    Wehkamp, Jan
    Schröder, Björn
    Schroeder, Jens M
    Morita, Eishin
    Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide.2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 42, p. 13039-44Article in journal (Refereed)
    Abstract [en]

    The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum-inhibiting activity from lesional psoriasis scale extracts and identified the Cys-reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn(2+), suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7-mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn(2+)-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn(2+)-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn(2+)-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi.

  • 133.
    Hernández, Sara B
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Environmental roles of microbial amino acid racemases2016In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 18, no 6, p. 1673-1685Article, review/survey (Refereed)
    Abstract [en]

    Enzymes catalysing the stereo-chemical inter-conversion of amino acids are known as amino acid racemases. In bacteria, these enzymes are fundamental to synthesize the D-Ala and D-Glu that are critical components of the peptidoglycan. In addition to this structural function in cell wall assembly, D-amino acids produced by microbial amino acid racemases have been described as relevant constituents in other prokaryotic structures (e.g. capsule, non-ribosomal peptides) and have been associated to growth fitness and to processes such as biofilm development, spore germination, and signalling. The recent discovery of broad spectrum racemases able to produce and release several D-amino acids to the environment suggests that these enzymes might have a great impact in microbial ecology. Consequently, new data on the biochemistry and regulation of racemases is key to understand the biological significance of D-enantiomers in nature, in particular their effect on microbial social networks. This review summarizes current knowledge on the environmental roles of bacterial racemases with an emphasis on the potential roles of the new broad spectrum enzymes in natural environments.

  • 134. Hernández, Sara B
    et al.
    Cava, Felipe
    Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.
    Pucciarelli, Maria Graciela
    García-Del Portillo, Francisco
    de Pedro, Miguel A
    Casadesús, Josep
    Bile-induced peptidoglycan remodeling in Salmonella enterica2015In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920, Vol. 17, no 4, p. 1081-1089Article in journal (Refereed)
    Abstract [en]

    Changes in the peptidoglycan (PG) structure of Salmonella enterica are detected in the presence of a sublethal concentration of sodium deoxycholate (DOC): (i) lower proportions of Braun lipoprotein (Lpp)-bound muropeptides; (ii) reduced levels of muropeptides cross-linked by L(meso)-diaminopimelyl-D(meso)-diaminopimelic acid (L-D) peptide bridges (3-3 cross-links). Similar structural changes are found in S. enterica cultures adapted to grow in the presence of a lethal concentration of DOC, suggesting that reduced anchoring of Braun protein to PG and low occurrence of 3-3 cross-links may increase S. enterica resistance to bile. This view is further supported by additional observations: (i) A triple mutant lacking L,D-transpeptidases YbiS, ErfK, and YcfS, which does not contain Lpp anchored to PG, is hyper-resistant to bile; (ii) enhanced 3-3 cross-linking upon overexpression of YnhG transpeptidase causes a decrease in bile resistance. These observations suggest that remodelling of the cell wall may be added to the list of adaptive responses that permit survival of S. enterica in the presence of bile.

  • 135.
    Hidalgo, Aurelio
    et al.
    Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica-CSIC.
    Betancor, Lorena
    Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica-CSIC.
    Moreno, Renata
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Zafra, Olga
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Cava, Felipe
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Fernández-Lafuente, Roberto
    Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica-CSIC.
    Guisán, José M
    Departamento de Biocatálisis, Instituto de Catálisis y Petroleoquímica-CSIC.
    Berenguer, José
    Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.
    Thermus thermophilus as a cell factory for the production of a thermophilic Mn-dependent catalase which fails to be synthesized in an active form in Escherichia coli2004In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 70, no 7, p. 3839-3844Article in journal (Refereed)
    Abstract [en]

    Thermostable Mn-dependent catalases are promising enzymes in biotechnological applications as H(2)O(2)-detoxifying systems. We cloned the genes encoding Mn-dependent catalases from Thermus thermophilus HB27 and HB8 and a less thermostable mutant carrying two amino acid replacements (M129V and E293G). When the wild-type and mutant genes were overexpressed in Escherichia coli, unmodified or six-His-tagged proteins of the expected size were overproduced as inactive proteins. Several attempts to obtain active forms or to activate the overproduced proteins were unsuccessful, even when soluble and thermostable proteins were used. Therefore, a requirement for a Thermus-specific activation factor was suggested. To overcome this problem, the Mn-dependent catalase genes were overexpressed directly in T. thermophilus under the control of the Pnar promoter. This promoter belongs to a respiratory nitrate reductase from of T. thermophilus HB8, whose transcription is activated by the combined action of nitrate and anoxia. Upon induction in T. thermophilus HB8, a 20- to 30-fold increase in catalase specific activity was observed, whereas a 90- to 110-fold increase was detected when the laboratory strain T. thermophilus HB27::nar was used as the host. The thermostability of the overproduced wild-type catalase was identical to that previously reported for the native enzyme, whereas decreased stability was detected for the mutant derivative. Therefore, our results validate the use of T. thermophilus as an alternative cell factory for the overproduction of thermophilic proteins that fail to be expressed in well-known mesophilic hosts.

  • 136. Holm, Kare Olav
    et al.
    Nilsson, Kristina
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Hjerde, Erik
    Willassen, Nils-Peder
    Milton, Debra L.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Complete genome sequence of Vibrio anguillarum strain NB10, a virulent isolate from the Gulf of Bothnia2015In: Standards in Genomic Sciences, ISSN 1944-3277, E-ISSN 1944-3277, Vol. 10, article id 60Article in journal (Refereed)
    Abstract [en]

    Vibrio anguillarum causes a fatal hemorrhagic septicemia in marine fish that leads to great economical losses in aquaculture world-wide. Vibrio anguillarum strain NB10 serotype O1 is a Gram-negative, motile, curved rod-shaped bacterium, isolated from a diseased fish on the Swedish coast of the Gulf of Bothnia, and is slightly halophilic. Strain NB10 is a virulent isolate that readily colonizes fish skin and intestinal tissues. Here, the features of this bacterium are described and the annotation and analysis of its complete genome sequence is presented. The genome is 4,373,835 bp in size, consists of two circular chromosomes and one plasmid, and contains 3,783 protein-coding genes and 129 RNA genes.

  • 137.
    Honn, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bharath, Gurram Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lack of OxyR and KatG Results in Extreme Susceptibility of Francisella tularensis LVS to Oxidative Stress and Marked Attenuation In vivo2017In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 7, article id 14Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis is an intracellular bacterium and as such is expected to encounter a continuous attack by reactive oxygen species (ROS) in its intracellular habitat and efficiently coping with oxidative stress is therefore essential for its survival. The oxidative stress response system of F tularensis is complex and includes multiple antioxidant enzymes and pathways, including the transcriptional regulator OxyR and the H2O2-decomposing enzyme catalase, encoded by katG. The latter is regulated by OxyR. A deletion of either of these genes, however, does not severely compromise the virulence of F tularensis and we hypothesized that if the bacterium would be deficient of both catalase and OxyR, then the oxidative defense and virulence of F tularensis would become severely hampered. To test this hypothesis, we generated a double deletion mutant, Delta oxyR/Delta katG, of F tularensis LVS and compared its phenotype to the parental LVS strain and the corresponding single deletion mutants. In accordance with the hypothesis, Delta oxyR/Delta katG was distinctly more susceptible than Delta oxyR and Delta katG to H2O2, ONOO-, and O-2(-), moreover, it hardly grew in mouse-derived BMDM or in mice, whereas Delta katG and Delta oxyR grew as well as F tularensis LVS in BMDM and exhibited only slight attenuation in mice. Altogether, the results demonstrate the importance of catalase and OxyR for a robust oxidative stress defense system and that they act cooperatively. The lack of both functions render F tularensis severely crippled to handle oxidative stress and also much attenuated for intracellular growth and virulence.

  • 138.
    Honn, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Lindgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    The role of MglA for adaptation to oxidative stress of Francisella tularensis LVS2012In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 12, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background: The Francisella tularensis protein MglA performs complex regulatory functions since it influences the expression of more than 100 genes and proteins in F. tularensis. Besides regulating the igl operon, it has been suggested that it also regulates several factors such as SspA, Hfq, CspC, and UspA, all important to stress adaptation. Therefore, it can be hypothesized that MglA plays an important role for Francisella stress responses in general and for the oxidative stress response specifically.

    Results: We investigated the oxidative stress response of the Delta mglA mutant of the live vaccine strain (LVS) of F. tularensis and found that it showed markedly diminished growth and contained more oxidized proteins than the parental LVS strain when grown in an aerobic milieu but not when grown microaerobically. Moreover, the Delta mglA mutant exhibited an increased catalase activity and reduced expression of the fsl operon and feoB in the aerobic milieu. The mutant was also found to be less susceptible to H2O2. The aberrant catalase activity and gene expression was partially normalized when the Delta mglA mutant was grown in a microaerobic milieu.

    Conclusions: Altogether the results show that the Delta mglA mutant exhibits all the hallmarks of a bacterium subjected to oxidative stress under aerobic conditions, indicating that MglA is required for normal adaptation of F. tularensis to oxidative stress and oxygen-rich environments.

  • 139.
    Hosseinzadeh, Ava
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kötemann, A
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Adenosine is a drugable negative regulator of neutrophil activity during Candida albicans infectionManuscript (preprint) (Other academic)
  • 140.
    Hosseinzadeh, Ava
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Thompson, Paul R.
    Segal, Brahm H.
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nicotine induces neutrophil extracellular traps2016In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 100, no 5, p. 1105-1112Article in journal (Refereed)
    Abstract [en]

    NETs serve to ensnare and kill microbial pathogens. However, NETs can at the same time contribute to tissue damage and excessive inflammation. Nicotine is a major toxic agent and has been associated with exacerbated inflammatory diseases. The current study aimed at investigating the role of nicotine, the addictive component of tobacco and electronic cigarettes, on triggering NET formation. We report that nicotine induces neutrophils to release NETs in a dose-dependent manner. Nicotine-induced NET formation is mediated via nicotine acetylcholine receptors, depends on Akt and PAD4 activation, but is Nox2-independent, as demonstrated by pharmacological inhibition of Nox2 and by use of Nox2-deficient mouse neutrophils. These findings demonstrate that nicotine induces NETs, which may in turn contribute to smoking-related diseases.

  • 141.
    Hugerth, Luisa W.
    et al.
    KTH Royal Institute of Technology.
    Larsson, John
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Alneberg, Johannes
    KTH Royal Institute of Technology.
    Lindh, Markus V.
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Legrand, Catherine
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Pinhassi, Jarone
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Andersson, Anders F.
    KTH Royal Institute of Technology.
    Metagenome-assembled genomes uncover a global brackish microbiome2015In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, article id 279Article in journal (Refereed)
    Abstract [en]

    Background: Microbes are main drivers of biogeochemical cycles in oceans and lakes. Although the genome is a foundation for understanding the metabolism, ecology and evolution of an organism, few bacterioplankton genomes have been sequenced, partly due to difficulties in cultivating them. Results: We use automatic binning to reconstruct a large number of bacterioplankton genomes from a metagenomic time-series from the Baltic Sea, one of world's largest brackish water bodies. These genomes represent novel species within typical freshwater and marine clades, including clades not previously sequenced. The genomes' seasonal dynamics follow phylogenetic patterns, but with fine-grained lineage-specific variations, reflected in gene-content. Signs of streamlining are evident in most genomes, and estimated genome sizes correlate with abundance variation across filter size fractions. Comparing thegenomes with globally distributed metagenomes reveals significant fragment recruitment at high sequence identity from brackish waters in North America, but little from lakes or oceans. This suggests the existence of a global brackish metacommunity whose populations diverged from freshwater and marine relatives over 100,000 years ago, long before the Baltic Sea was formed (8000 years ago). This markedly contrasts to most Baltic Sea multicellular organisms, which are locally adapted populations of freshwater or marine counterparts. Conclusions: We describe the gene content, temporal dynamics and biogeography of a large set of new bacterioplankton genomes assembled from metagenomes. We propose that brackish environments exert such strong selection that lineages adapted to them flourish globally with limited influence from surrounding aquatic communities.

  • 142.
    Hultmark, Dan
    Stockholms universitet, mikrobiologiska institutionen.
    Insect immunity: Inducible antibacterial proteins from Hyalophora cecropia1982Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A powerful bactericidal activity can be induced in the hemolymph of many insects as a response to an injection of bacteria. The nature of the effector molecules of this immune response was investigated, using pupae of the Cecropia moth, Hyalophora cecropia. Three major types of antibacterial proteins were found: the cecropins, the P5 proteins, and lysozyme. They appear in the hemolymph as a result of de novo synthesis.Six different cecropins were purified and characterized. The full amino acid sequences of the three major cecropins A, B and D were determined, as well as partial sequences of the three minor cecropins C, E and F. The cecropins are all very small (Mr = 4,000) and basic (pI > 9.5) proteins, and they show extensive homology in their sequences. The three major cecropins are products of different genes. Their C-terminals are blocked by uncharged groups, which can be removed by mild acid hydrolysis. The minor cecropins are closely related to the major forms, and may be unblocked precursors or, in one case (cecropin F), a minor allelic form. The cecropins were shown to be lytic, and to be efficient against several Gram positive and Gram negative bacterial strains, but not against mammalian cells.The P5 proteins are bactericidal proteins, larger than the cecropins (Mr = 20,000 - 23,000). Six forms, differing in isoelectric point, were isolated. They form two closely related groups, the basic (P5 A-D) and the acidic forms (P5 E-F). Within each group, the different forms have almost identical amino acid compositions.The Cecropia lysozyme is similar to lysozymes isolated from other insects, as well as to that from hen egg white. It is lytic to a restricted number of Gram positive bacteria.The presence of cecropins and other antibacterial factors was demon-strated also in other lepidopterans, notably Galleria mellonella, and may explain earlier observations of antibacterial factors in the latter species.

  • 143.
    Huseby, Siv
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Wikner, Johan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Bacterial growth2018Report (Other academic)
    Abstract [en]

    Bacterioplankton growth rate is an indicator of the decomposition of organic matter and thereby trophic status of the Sea. The bacterioplankton metabolism accounts for about half of the mineralization of organic matter and thereby pelagic oxygen consumption.

    The bacterioplankton growth rate in deep waters indicates good trophic status in the off-shore Bothnian Bay and Bothnian Sea. Deep water growth rates were 67 % higher than at corresponding depths in the Atlantic Ocean, lacking excess enrichment. The decline that has earlier been reported has now ceased. During the last few years the growth rates has increased some and there is now no significant trends in any of the studied basins.

  • 144. Hägglund, Moa
    et al.
    Bäckman, Stina
    Macellaro, Anna
    Lindgren, Fetter
    Borgmästars, Emmy
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jacobsson, Karin
    Dryselius, Rikard
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI, Swedish Defence Research Agency, Umeå, Sweden.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Division of CBRN Security and Defence, FOI, Swedish Defence Research Agency, Umeå, Sweden.
    Forsman, Mats
    Ahlinder, Jon
    Accounting for bacterial overlap between raw water communities and contaminating sources improves the accuracy of signature-based microbial source tracking2018In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 2364Article in journal (Refereed)
    Abstract [en]

    Microbial source tracking (MST) analysis is essential to identifying and mitigating the fecal pollution of water resources. The signature-based MST method uses a library of sequences to identify contaminants based on operational taxonomic units (OTUs) that are unique to a certain source. However, no clear guidelines for how to incorporate OTU overlap or natural variation in the raw water bacterial community into MST analyses exist. We investigated how the inclusion of bacterial overlap between sources in the library affects source prediction accuracy. To achieve this, large-scale sampling-including feces from seven species, raw sewage, and raw water samples from water treatment plants - was followed by 16S rRNA amplicon sequencing. The MST library was defined using three settings: (i) no raw water communities represented; (ii) raw water communities selected through clustering analysis; and (iii) local water communities collected across consecutive years. The results suggest that incorporating either the local background or representative bacterial composition improves MST analyses, as the results were positively correlated to measured levels of fecal indicator bacteria and the accuracy at which OTUs were assigned to the correct contamination source increased fourfold. Using the proportion of OTUs with high source origin probability, underpinning a contaminating signal, is a solid foundation in a framework for further deciphering and comparing contaminating signals derived in signature-based MST approaches. In conclusion, incorporating background bacterial composition of water in MST can improve mitigation efforts for minimizing the spread of pathogenic and antibiotic resistant bacteria into essential freshwater resources.

  • 145.
    Ihalin, Riikka
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Department of Biochemistry, University of Turku, Turku, Finland.
    Zhong, Deyu
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Department of Periodontics, Stomatological Hospital, Southern Medical University, Guangzhou, People’s Republic of China.
    Karched, Maribasappa
    Chen, Casey
    Asikainen, Sirkka
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Phosphorylcholine is located in Aggregatibacter actinomycetemcomitans fimbrial protein Flp 12018In: Medical Microbiology and Immmunology, ISSN 0300-8584, E-ISSN 1432-1831, Vol. 207, no 5-6, p. 329-338Article in journal (Refereed)
    Abstract [en]

    Phosphorylcholine (ChoP) is covalently incorporated into bacterial surface structures, contributing to host mimicry and promoting adhesion to surfaces. Our aims were to determine the frequency of ChoP display among Aggregatibacter actinomycetemcomitans strains, to clarify which surface structures bear ChoP, and whether ChoP-positivity relates to serum killing. The tested oral (N=67) and blood isolates (N=27) represented 6 serotypes. Mab TEPC-15 was used for immunoblotting of cell lysates and fractions and for immunofluorescence microscopy of cell surface-bound ChoP. The lysates were denatured with urea for hidden ChoP or treated with proteinase K to test whether it binds to a protein. Three ChoP-positive and two ChoP-negative strains were subjected to serum killing in the presence/absence of CRP and using Ig-depleted serum as complement source. Cell lysates and the first soluble cellular fraction revealed a<10kDa band in immunoblots. Among 94 strains, 27 were ChoP positive. No difference was found in the prevalence of ChoP-positive oral (21/67) and blood (6/27) strains. Immunofluorescence microscopy corresponded to the immunoblot results. Proteinase K abolished ChoP reactivity, whereas urea did not change the negative result. The TEPC-15-reactive protein was undetectable in flp1 mutant strain. The survival rate of serotype-b strains in serum was 100% irrespective of ChoP, but that of serotype-a was higher in ChoP-positive (85%) than ChoP-negative (71%) strains. The results suggest that a third of rough-colony strains harbor ChoP and that ChoP is attached to fimbrial subunit protein Flp1. It further seems that ChoP-positivity does not enhance but may reduce A. actinomycetemcomitans susceptibility to serum killing.

  • 146.
    Irazoki, Oihane
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hernandez, Sara B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Peptidoglycan Muropeptides: Release, Perception, and Functions as Signaling Molecules2019In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 500Article, review/survey (Refereed)
    Abstract [en]

    Peptidoglycan (PG) is an essential molecule for the survival of bacteria, and thus, its biosynthesis and remodeling have always been in the spotlight when it comes to the development of antibiotics. The peptidoglycan polymer provides a protective function in bacteria, but at the same time is continuously subjected to editing activities that in some cases lead to the release of peptidoglycan fragments (i.e., muropeptides) to the environment. Several soluble muropeptides have been reported to work as signaling molecules. In this review, we summarize the mechanisms involved in muropeptide release (PG breakdown and PG recycling) and describe the known PG-receptor proteins responsible for PG sensing. Furthermore, we overview the role of muropeptides as signaling molecules, focusing on the microbial responses and their functions in the host beyond their immunostimulatory activity.

  • 147.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, p. 779-788Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.

  • 148.
    Ishikawa, Takahiko
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rompikuntal, Pramod Kumar
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lindmark, Barbro
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Milton, Debra L.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wai, Sun Nyunt
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Quorum sensing regulation of the two hcp alleles in Vibrio cholerae O1 strains2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 8, article id e6734Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The type VI secretion system (T6SS) has emerged as a protein secretion system important to several gram-negative bacterial species. One of the common components of the system is Hcp, initially described as a hemolysin co-regulated protein in a serotype O17 strain of Vibrio cholerae. Homologs to V. cholerae hcp genes have been found in all characterized type VI secretion systems and they are present also in the serotype O1 strains of V. cholerae that are the cause of cholera diseases but seemed to have non-functional T6SS.

    METHODOLOGY/PRINCIPAL FINDINGS: The serotype O1 V. cholerae strain A1552 was shown to express detectable levels of Hcp as determined by immunoblot analyses using polyclonal anti-Hcp antiserum. We found that the expression of Hcp was growth phase dependent. The levels of Hcp in quorum sensing deficient mutants of V. cholerae were compared with the levels in wild type V. cholerae O1 strain A1552. The expression of Hcp was positively and negatively regulated by the quorum sensing regulators HapR and LuxO, respectively. In addition, we observed that expression of Hcp was dependent on the cAMP-CRP global transcriptional regulatory complex and required the RpoN sigma factor.

    CONCLUSION/SIGNIFICANCE: Our results show that serotype O1 strains of V. cholerae do express Hcp which is regarded as one of the important T6SS components and is one of the secreted substrates in non-O1 non-O139 V. cholerae isolates. We found that expression of Hcp was strictly regulated by the quorum sensing system in the V. cholerae O1 strain. In addition, the expression of Hcp required the alternative sigma factor RpoN and the cAMP-CRP global regulatory complex. Interestingly, the environmental isolates of V. cholerae O1 strains that showed higher levels of the HapR quorum sensing regulator in comparison with our laboratory standard serotype O1 strain A1552 where also expressing higher levels of Hcp.

  • 149.
    Jahns, Anika C.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eilers, Hinnerk
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Transcriptomic analysis of Propionibacterium acnes biofilms in vitro2016In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 42, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Propionibacterium acnes is a well-known commensal of the human skin connected to acne vulgaris and joint infections. It is extensively studied in planktonic cultures in the laboratory settings but occurs naturally in biofilms. In this study we have developed an in vitro biofilm model of P. acnes and studied growth features, matrix composition, matrix penetration by fluorescent-labeled antibiotics as well as gene expression. Antibiotic susceptibility of biofilms was studied and could be enhanced by increased glucose concentrations. Biofilm cells were characterized by up-regulated stress-induced genes and up regulation of genes coding for the potential virulence-associated CAMP factors. P. acnes can generate persister cells showing a reversible tolerance to 50 fold MIC of common antibiotics.

  • 150. Jain, Vibhu
    et al.
    Dongre, Mitesh
    Raychaudhuri, Saumya
    Interaction of Vibrio cholerae O139 with an intestinal parasite, Entamoeba histolytica.2006In: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, no Pt 12, p. 1755-6Article in journal (Refereed)
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