Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Alternative names
Publications (10 of 13) Show all publications
Lopez Chiloeches, M., Bergonzini, A., Martin, O. C. B., Bergstein, N., Erttmann, S. F., Aung, K. M., . . . Frisan, T. (2023). Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes. Frontiers in Immunology, 14, Article ID 1270449.
Open this publication in new window or tab >>Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes
Show others...
2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1270449Article in journal (Refereed) Published
Abstract [en]

Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.

Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.

Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.

Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
bacterial genotoxin, DNA damage response, inflammasome, inflammation, tissue specificity
National Category
Immunology Microbiology
Identifiers
urn:nbn:se:umu:diva-220315 (URN)10.3389/fimmu.2023.1270449 (DOI)001150445700001 ()38274797 (PubMedID)2-s2.0-85183041210 (Scopus ID)
Funder
Swedish Cancer Society, 20 0699 PjFSwedish Research Council, 2021-00960The Kempe Foundations, SMK-1962The Kempe Foundations, JCK-1826The Kempe Foundations, JCK-3110Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Erttmann, S. F. & Gekara, N. O. (2023). Protocol for isolation of microbiota-derived membrane vesicles from mouse blood and colon. STAR Protocols, 4(1), Article ID 102046.
Open this publication in new window or tab >>Protocol for isolation of microbiota-derived membrane vesicles from mouse blood and colon
2023 (English)In: STAR Protocols, E-ISSN 2666-1667, Vol. 4, no 1, article id 102046Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
CellPress, 2023
Keywords
Cell Separation/Fractionation, Immunology, Microbiology, Model Organisms
National Category
Cell and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-204527 (URN)10.1016/j.xpro.2023.102046 (DOI)2-s2.0-85146709627 (Scopus ID)
Funder
Stockholm UniversitySwedish Research Council, 2016-00890Swedish Research Council, 2022-01308Swedish Cancer Society, 20 1252 PjFUmeå UniversityThe Kempe Foundations, SMK-1858.2Åke Wiberg Foundation, M19-0314Swedish Cancer Society, CAN 2017/421
Available from: 2023-02-06 Created: 2023-02-06 Last updated: 2023-02-06Bibliographically approved
Erttmann, S. F., Swacha, P., Aung, K. M., Brindefalk, B., Jiang, H., Härtlova, A., . . . Gekara, N. O. (2022). The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity, 55(5), 847-861
Open this publication in new window or tab >>The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis
Show others...
2022 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 55, no 5, p. 847-861Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Cell Press, 2022
Keywords
bacterial membrane vesicles, cGAS, infections, innate immunity, interferons, microbiota, pattern recognition receptors, STING, virus
National Category
Microbiology in the medical area Immunology
Identifiers
urn:nbn:se:umu:diva-194835 (URN)10.1016/j.immuni.2022.04.006 (DOI)000802171100010 ()35545033 (PubMedID)2-s2.0-85129773156 (Scopus ID)
Funder
Swedish Cancer Society, 2017/419Swedish Cancer Society, 2017/421Åke Wiberg Foundation, M19-0314Swedish Research Council, 2015-02857Swedish Research Council, 2015-03007Swedish Research Council, 2015-06824Swedish Research Council, 2016-00890Swedish Research Council, 2016-06598Swedish Research Council, 2018-02914Swedish Research Council, 2019-01720
Available from: 2022-05-31 Created: 2022-05-31 Last updated: 2023-09-05Bibliographically approved
Nilsson, J., Hörnberg, M., Schmidt-Christensen, A., Linde, K., Nilsson, M., Carlus, M., . . . Holmberg, D. (2020). NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis. Scientific Reports, 10(1), Article ID 21778.
Open this publication in new window or tab >>NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis
Show others...
2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 21778Article in journal (Refereed) Published
Abstract [en]

Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4αβNOD.Rag2−/− mice, but not in  2,4αβNOD.Rag2+/− control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation.

Place, publisher, year, edition, pages
Nature Research, 2020
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-178336 (URN)10.1038/s41598-020-78688-2 (DOI)000599945100005 ()33311540 (PubMedID)2-s2.0-85097369222 (Scopus ID)
Available from: 2021-01-12 Created: 2021-01-12 Last updated: 2022-09-15Bibliographically approved
Swacha, P., Gekara, N. O. & Erttmann, S. F. (2019). Biochemical and microscopic analysis of inflammasome complex formation. In: Jungsan Sohn (Ed.), DNA Sensors and Inflammasomes: (pp. 287-298). Elsevier, 625, Article ID S0076-6879(19)30173-9.
Open this publication in new window or tab >>Biochemical and microscopic analysis of inflammasome complex formation
2019 (English)In: DNA Sensors and Inflammasomes / [ed] Jungsan Sohn, Elsevier, 2019, Vol. 625, p. 287-298, article id S0076-6879(19)30173-9Chapter in book (Refereed)
Abstract [en]

Inflammasomes are multiprotein signaling platforms responsible for the maturation of pro-IL-1β and pro-IL-18 as well as the induction of an inflammatory cell death termed pyroptosis. Most inflammasomes consist of an upstream sensor, in most cases an adaptor protein (ASC) and inflammatory caspases such as caspase-1. Upon activation, sensor proteins oligomerize with adaptor proteins, forming large complexes called specks. These complexes can be stabilized and detected by Western blotting or fluorescence microscopy providing a direct evidence of inflammasome activation. Here we describe protocols for two complementary methods for detecting inflammasome complexes: (1) biochemical isolation and detection of ASC oligomers by Western blot analysis and (2) microscopic visualization of active caspase-1—ASC complexes. These protocols have successfully been applied in our recent study to unveil new regulatory mechanisms for different inflammasomes including the DNA sensor AIM2 (Erttmann et al., 2016).

Place, publisher, year, edition, pages
Elsevier, 2019
Series
Methods in Enzymology, ISSN 0076-6879 ; 625
Keywords
Inflammasome complex, ASC specks, Caspase 1, AIM2, IL-1β, Innate immunity
National Category
Cell and Molecular Biology
Research subject
Immunology; cell research; Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-162825 (URN)10.1016/bs.mie.2019.05.014 (DOI)000488782900018 ()31455532 (PubMedID)2-s2.0-85067031234 (Scopus ID)978-0-12-818359-5 (ISBN)
Available from: 2019-08-30 Created: 2019-08-30 Last updated: 2023-03-23Bibliographically approved
Erttmann, S. F. & Gekara, N. O. (2019). Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity. Nature Communications, 10, Article ID 3493.
Open this publication in new window or tab >>Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity
2019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 3493Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
Keywords
Inflammasome
National Category
Cell and Molecular Biology
Research subject
Immunology; cell research; Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-162589 (URN)10.1038/s41467-019-11169-x (DOI)000478576800011 ()31375698 (PubMedID)2-s2.0-85070100317 (Scopus ID)
Available from: 2019-08-23 Created: 2019-08-23 Last updated: 2023-03-28Bibliographically approved
Bamyaci, S., Ekestubbe, S., Nordfelth, R., Erttmann, S. F., Edgren, T. & Forsberg, Å. (2018). YopN Is Required for Efficient Effector Translocation and Virulence in Yersinia pseudotuberculosis. Infection and Immunity, 86(8), Article ID e00957-17.
Open this publication in new window or tab >>YopN Is Required for Efficient Effector Translocation and Virulence in Yersinia pseudotuberculosis
Show others...
2018 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 86, no 8, article id e00957-17Article in journal (Refereed) Published
Abstract [en]

Type III secretion systems (T3SSs) are used by various Gram-negative pathogens to subvert the host defense by a host cell contact-dependent mechanism to secrete and translocate virulence effectors. While the effectors differ between pathogens and determine the pathogenic life style, the overall mechanism of secretion and translocation is conserved. T3SSs are regulated at multiple levels, and some secreted substrates have also been shown to function in regulation. In Yersinia, one of the substrates, YopN, has long been known to function in the host cell contact-dependent regulation of the T3SS. Prior to contact, through its interaction with TyeA, YopN blocks secretion. Upon cell contact, TyeA dissociates from YopN, which is secreted by the T3SS, resulting in the induction of the system. YopN has also been shown to be translocated into target cells by a T3SS-dependent mechanism. However, no intracellular function has yet been assigned to YopN. The regulatory role of YopN involves the N-terminal and C-terminal parts, while less is known about the role of the central region of YopN. Here, we constructed different in-frame deletion mutants within the central region. The deletion of amino acids 76 to 181 resulted in an unaltered regulation of Yop expression and secretion but triggered reduced YopE and YopH translocation within the first 30 min after infection. As a consequence, this deletion mutant lost its ability to block phagocytosis by macrophages. In conclusion, we were able to differentiate the function of YopN in translocation and virulence from its function in regulation.

Keywords
phagocytosis, type III secretion, Yersinia, YopN, virulence
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-150354 (URN)10.1128/IAI.00957-17 (DOI)000439474900006 ()29760214 (PubMedID)2-s2.0-85054934435 (Scopus ID)
Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2023-03-23Bibliographically approved
Wang, H., Avican, K., Fahlgren, A., Erttmann, S. F., Nuss, A. M., Dersch, P., . . . Wolf-Watz, H. (2016). Increased plasmid copy number is essential for Yersinia T3SS function and virulence. Science, 353(6298), 492-495
Open this publication in new window or tab >>Increased plasmid copy number is essential for Yersinia T3SS function and virulence
Show others...
2016 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 353, no 6298, p. 492-495Article in journal (Refereed) Published
Abstract [en]

Pathogenic bacteria have evolved numerous virulence mechanisms that are essential for establishing infections. The enterobacterium Yersinia uses a type III secretion system (T3SS) encoded by a 70-kilobase, low-copy, IncFII-class virulence plasmid. We report a novel virulence strategy in Y. pseudotuberculosis in which this pathogen up-regulates the plasmid copy number during infection. We found that an increased dose of plasmid-encoded genes is indispensable for virulence and substantially elevates the expression and function of the T3SS. Remarkably, we observed direct, tight coupling between plasmid replication and T3SS function. This regulatory pathway provides a framework for further exploration of the environmental sensing mechanisms of pathogenic bacteria.

National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-125586 (URN)10.1126/science.aaf7501 (DOI)000380583600042 ()27365311 (PubMedID)2-s2.0-84976871025 (Scopus ID)
Available from: 2016-09-19 Created: 2016-09-13 Last updated: 2023-03-24Bibliographically approved
Erttmann, S. F., Härtlova, A., Sloniecka, M., Raffi, F. A. M., Hosseinzadeh, A., Edgren, T., . . . Gekara, N. O. (2016). Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity. Immunity, 45(1), 106-118
Open this publication in new window or tab >>Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity
Show others...
2016 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 45, no 1, p. 106-118Article in journal (Refereed) Published
Abstract [en]

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

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-125590 (URN)10.1016/j.immuni.2016.06.018 (DOI)000380749000014 ()27421701 (PubMedID)2-s2.0-84990818455 (Scopus ID)
Available from: 2016-09-23 Created: 2016-09-13 Last updated: 2024-04-11Bibliographically approved
Härtlova, A., Erttmann, S. F., Raffi, F. A. M., Schmalz, A. M., Resch, U., Anugula, S., . . . Gekara, N. O. (2015). DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity. Immunity, 42(2), 332-343
Open this publication in new window or tab >>DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity
Show others...
2015 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 42, no 2, p. 332-343Article in journal (Refereed) Published
Abstract [en]

Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-101396 (URN)10.1016/j.immuni.2015.01.012 (DOI)000349916400016 ()25692705 (PubMedID)2-s2.0-84922986861 (Scopus ID)
Available from: 2015-07-02 Created: 2015-03-30 Last updated: 2023-03-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2398-8405

Search in DiVA

Show all publications