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Golovliov, Igor
Alternative names
Publications (10 of 27) Show all publications
Lindgren, H., Eneslätt, K., Golovliov, I., Gelhaus, C. & Sjöstedt, A. (2023). Analyses of human immune responses to Francisella tularensis identify correlates of protection. Frontiers in Immunology, 14, Article ID 1238391.
Open this publication in new window or tab >>Analyses of human immune responses to Francisella tularensis identify correlates of protection
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1238391Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is the etiological agent of the potentially severe infection tularemia. An existing F: tularensis vaccine, the live vaccine strain (LVS), has been used to protect at-risk personnel, but it is not licensed in any country and it has limited efficacy. Therefore, there is a need of a new, efficacious vaccine. The aim of the study was to perform a detailed analysis of the characteristics of the human immune response to F. tularensis, since this will generate crucial knowledge required to develop new vaccine candidates. Nine individuals were administered the LVS vaccine and peripheral blood mononuclear cells (PBMC) were collected before and at four time points up to one year after vaccination. The properties of the PBMC were characterized by flow cytometry analysis of surface markers and intracellular cytokine staining. In addition, the cytokine content of supernatants from F. tularensis-infected PBMC cultures was determined and the protective properties of the supernatants investigated by adding them to cultures with infected monocyte-derived macrophages (MDM). Unlike before vaccination, PBMC collected at all four time points after vaccination demonstrated F. tularensis-specific cell proliferation, cytokine secretion and cytokine-expressing memory cells. A majority of 17 cytokines were secreted at higher levels by PBMC collected at all time points after vaccination than before vaccination. A discriminative analysis based on IFN-γ and IL-13 secretion correctly classified samples obtained before and after vaccination. Increased expression of IFN-γ, IL-2, and MIP-1β were observed at all time points after vaccination vs. before vaccination and the most significant changes occurred among the CD4 transient memory, CD8 effector memory, and CD8 transient memory T-cell populations. Growth restriction of the highly virulent F. tularensis strain SCHU S4 in MDM was conferred by supernatants and protection correlated to levels of IFN-γ, IL-2, TNF, and IL-17. The findings demonstrate that F. tularensis vaccination induces long-term T-cell reactivity, including TEM and TTM cell populations. Individual cytokine levels correlated with the degree of protection conferred by the supernatants. Identification of such memory T cells and effector mechanisms provide an improved understanding of the protective mechanisms against F. tularensis. mechanisms against F. tularensis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
F. tularensis, human correlates of protection, immune response, memory cells, vaccination
National Category
Immunology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-215234 (URN)10.3389/fimmu.2023.1238391 (DOI)37781364 (PubMedID)2-s2.0-85173061344 (Scopus ID)
Funder
Region Västerbotten, RV-939171Region Västerbotten, RV-941049
Available from: 2023-10-16 Created: 2023-10-16 Last updated: 2024-01-17Bibliographically approved
Chin, C.-Y., Zhao, J., Llewellyn, A. C., Golovliov, I., Sjöstedt, A., Zhou, P. & Weiss, D. S. (2021). Francisella FlmX broadly affects lipopolysaccharide modification and virulence. Cell Reports, 35(11), Article ID 109247.
Open this publication in new window or tab >>Francisella FlmX broadly affects lipopolysaccharide modification and virulence
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 11, article id 109247Article in journal (Refereed) Published
Abstract [en]

The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the surprising convergence of these pathways through FlmX, an uncharacterized protein in the intracellular pathogen Francisella. FlmX is in the flippase family, which includes proteins that traffic lipid-linked envelope components across membranes. flmX deficiency causes defects in lipid A modification, core remodeling, and O-antigen addition. We find that an F. tularensis mutant lacking flmX is >1,000,000-fold attenuated. Furthermore, FlmX is required to resist the innate antimicrobial LL-37 and the antibiotic polymyxin. Given FlmX's central role in LPS modification and its conservation in intracellular pathogens Brucella, Coxiella, and Legionella, FlmX may represent a novel drug target whose inhibition could cripple bacterial virulence and sensitize bacteria to innate antimicrobials and antibiotics.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
cationic antimicrobial peptide, flippase, lipid A, lipopolysaccharide, polymyxin resistance
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-186362 (URN)10.1016/j.celrep.2021.109247 (DOI)000661869600009 ()34133919 (PubMedID)2-s2.0-85107905377 (Scopus ID)
Funder
NIH (National Institute of Health), AI098800, I01 BX002788Swedish Research Council, 2013-4581, 2013-8621
Available from: 2021-07-23 Created: 2021-07-23 Last updated: 2024-01-17Bibliographically approved
Golovliov, I., Bäckman, S., Granberg, M., Salomonsson, E., Lundmark, E., Näslund, J., . . . Thelaus, J. (2021). Long-Term Survival of Virulent Tularemia Pathogens outside a Host in Conditions That Mimic Natural Aquatic Environments. Applied and Environmental Microbiology, 87(6), 1-11, Article ID e02713-20.
Open this publication in new window or tab >>Long-Term Survival of Virulent Tularemia Pathogens outside a Host in Conditions That Mimic Natural Aquatic Environments
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2021 (English)In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 87, no 6, p. 1-11, article id e02713-20Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis, the causative agent of the zoonotic disease tularemia, can cause seasonal outbreaks of acute febrile illness in humans with disease peaks in late summer to autumn. Interestingly, its mechanisms for environmental persistence between outbreaks are poorly understood. One hypothesis is that F. tularensis forms biofilms in aquatic environments. We utilized two fully virulent wild-type strains: FSC200 (Francisella tularensis subsp. holarctica) and Schu S4 (Francisella tularensis subsp. tularensis) and three control strains, the attenuated live vaccine strain (LVS; F. tularensis subsp. holarctica), a Schu S4 DwbtI mutant that is documented to form biofilms, and the low-virulence strain U112 of the closely related species Francisella novicida. Strains were incubated in saline solution (0.9% NaCl) microcosms for 24 weeks at both 4°C and 20°C, whereupon viability and biofilm formation were measured. These temperatures were selected to approximate winter and summer temperatures of fresh water in Scandinavia, respectively. U112 and Schu S4 DwbtI formed biofilms, but F. tularensis strains FSC200 and Schu S4 and the LVS did not. All strains exhibited prolonged viability at 4°C compared to 20°C. U112 and FSC200 displayed remarkable long-term persistence at 4°C, with only 1- and 2-fold log reductions, respectively, of viable cells after 24weeks. Schu S4 exhibited lower survival, yielding no viable cells by week 20. At 24weeks, cells from FSC200, but not from Schu S4, were still fully virulent in mice. Taken together, these results demonstrate biofilm-independent, long-term survival of pathogenic F. tularensis subsp. holarctica in conditions that mimic overwinter survival in aquatic environments.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
aquatic environment, biofilms, Francisella tularensis, long-term persistence, tularemia
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-181734 (URN)10.1128/AEM.02713-20 (DOI)000623325400034 ()2-s2.0-85102078396 (Scopus ID)
Available from: 2021-03-23 Created: 2021-03-23 Last updated: 2023-09-05Bibliographically approved
Sheshko, V., Link, M., Golovliov, I., Balonova, L. & Stulik, J. (2021). Utilization of a tetracycline-inducible system for high-level expression of recombinant proteins in Francisella tularensis LVS. Plasmid, 115, Article ID 102564.
Open this publication in new window or tab >>Utilization of a tetracycline-inducible system for high-level expression of recombinant proteins in Francisella tularensis LVS
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2021 (English)In: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 115, article id 102564Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a Gram-negative intracellular pathogen causing tularemia. A number of its potential virulence factors have been identified, but their biology and functions are not precisely known. Understanding the biological and immunological functions of these proteins requires adequate genetic tools for homologous and heterologous expression of cloned genes, maintaining both original structure and post-translational modifications. Here, we report the construction of a new multipurpose shuttle plasmid – pEVbr – which can be used for high-level expression in F. tularensis. The pEVbr plasmid has been constructed by modifying the TetR-regulated expression vector pEDL17 (LoVullo, 2012) that includes (i) a strong F. tularensis bfr promoter, and (ii) two tet operator sequences cloned into the promoter. The cloned green fluorescent protein (GFP), used as a reporter, demonstrated almost undetectable basal expression level under uninduced conditions and a highly dynamic dose-dependent response to the inducer. The utility of the system was further confirmed by cloning the gapA and FTT_1676 genes into the pEVbr vector and quantifying proteins expression in F. tularensis LVS, as well as by studying post-translational modification of the cloned genes. This study demonstrates that high levels of recombinant native-like Francisella proteins can be produced in Francisella cells. Hence, this system may be beneficial for the analysis of protein function and the development of new treatments and vaccines.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
ATc inducible, Expression plasmid, Francisella tularensis, Regulated bfr promoter
National Category
Biochemistry and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-181586 (URN)10.1016/j.plasmid.2021.102564 (DOI)000649111200005 ()2-s2.0-85101554649 (Scopus ID)
Available from: 2021-03-19 Created: 2021-03-19 Last updated: 2023-09-05Bibliographically approved
Alam, A., Golovliov, I., Javed, E., Kumar, R., Ådén, J. & Sjöstedt, A. (2020). Dissociation between the critical role of ClpB of Francisella tularensis for the heat shock response and the DnaK interaction and its important role for efficient type VI secretion and bacterial virulence. PLoS Pathogens, 16(4), 1-27, Article ID e1008466.
Open this publication in new window or tab >>Dissociation between the critical role of ClpB of Francisella tularensis for the heat shock response and the DnaK interaction and its important role for efficient type VI secretion and bacterial virulence
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2020 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 16, no 4, p. 1-27, article id e1008466Article in journal (Refereed) Published
Abstract [en]

Author summary Type VI secretion systems (T6SSs) are essential virulence determinants of many Gram-negative pathogens, including Francisella tularensis. This highly virulent bacterium encodes an atypical T6SS lacking ClpV, the ATPase crucial for prototypic T6SS sheath disassembly. It, however, possesses ClpB, a protein critical for heat shock survival via its interaction with DnaK. Since ClpB possesses ATPase activity, it has been hypothesized to provide a compensatory function for the absence of ClpV, a hypothesis supported by the recent findings from us and others. Here, we investigated how F. tularensis ClpB controls T6S. In silico modelling of the ClpB-DnaK complex identified key interactions that were experimentally verified. For example, mutating one of the DnaK-interacting residues rendered the bacterium exquisitely susceptible to heat shock, but had no effect on T6S and virulence. In contrast, removing the N-terminal of ClpB only had a slight effect on the heat shock response, but strongly compromised both T6S and virulence. Intriguingly, the Escherichia coli ClpB could fully complement the function of F. tularensis ClpB. The data demonstrate that the two critical roles of ClpB, mediating heat shock survival and effective T6S, are dissociated and that the N-terminal is crucial for T6S and virulence. Francisella tularensis, a highly infectious, intracellular bacterium possesses an atypical type VI secretion system (T6SS), which is essential for its virulence. The chaperone ClpB, a member of the Hsp100/Clp family, is involved in Francisella T6SS disassembly and type VI secretion (T6S) is impaired in its absence. We asked if the role of ClpB for T6S was related to its prototypical role for the disaggregation activity. The latter is dependent on its interaction with the DnaK/Hsp70 chaperone system. Key residues of the ClpB-DnaK interaction were identified by molecular dynamic simulation and verified by targeted mutagenesis. Using such targeted mutants, it was found that the F. novicida ClpB-DnaK interaction was dispensable for T6S, intracellular replication, and virulence in a mouse model, although essential for handling of heat shock. Moreover, by mutagenesis of key amino acids of the Walker A, Walker B, and Arginine finger motifs of each of the two Nucleotide-Binding Domains, their critical roles for heat shock, T6S, intracellular replication, and virulence were identified. In contrast, the N-terminus was dispensable for heat shock, but required for T6S, intracellular replication, and virulence. Complementation of the Delta clpB mutant with a chimeric F. novicida ClpB expressing the N-terminal of Escherichia coli, led to reconstitution of the wild-type phenotype. Collectively, the data demonstrate that the ClpB-DnaK interaction does not contribute to T6S, whereas the N-terminal and NBD domains displayed critical roles for T6S and virulence.

Place, publisher, year, edition, pages
Public Library of Science, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-171909 (URN)10.1371/journal.ppat.1008466 (DOI)000531365400029 ()32275693 (PubMedID)2-s2.0-85084105089 (Scopus ID)
Available from: 2020-06-17 Created: 2020-06-17 Last updated: 2023-03-23Bibliographically approved
Mohammadi, N., Lindgren, H., Golovliov, I., Eneslätt, K., Yamamoto, M., Martin, A., . . . Sjöstedt, A. (2020). Guanylate-Binding Proteins Are Critical for Effective Control of Francisella tularensis Strains in a Mouse Co-Culture System of Adaptive Immunity. Frontiers in Cellular and Infection Microbiology, 10, Article ID 594063.
Open this publication in new window or tab >>Guanylate-Binding Proteins Are Critical for Effective Control of Francisella tularensis Strains in a Mouse Co-Culture System of Adaptive Immunity
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2020 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 10, article id 594063Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a Select Agent that causes the severe disease tularemia in humans and many animal species. The bacterium demonstrates rapid intracellular replication, however, macrophages can control its replication if primed and activation with IFN-γ is known to be essential, although alone not sufficient, to mediate such control. To further investigate the mechanisms that control intracellular F. tularensis replication, an in vitro co-culture system was utilized containing splenocytes obtained from naïve or immunized C57BL/6 mice as effectors and infected bone marrow-derived wild-type or chromosome-3-deficient guanylate-binding protein (GBP)-deficient macrophages. Cells were infected either with the F. tularensis live vaccine strain (LVS), the highly virulent SCHU S4 strain, or the surrogate for F. tularensis, F. novicida. Regardless of strain, significant control of the bacterial replication was observed in co-cultures with wild-type macrophages and immune splenocytes, but not in cultures with immune splenocytes and GBPchr3-deficient macrophages. Supernatants demonstrated very distinct, infectious agent-dependent patterns of 23 cytokines, whereas the cytokine patterns were only marginally affected by the presence or absence of GBPs. Levels of a majority of cytokines were inversely correlated to the degree of control of the SCHU S4 and LVS infections, but this was not the case for the F. novicida infection. Collectively, the co-culture assay based on immune mouse-derived splenocytes identified a dominant role of GBPs for the control of intracellular replication of various F. tularensis strains, regardless of their virulence, whereas the cytokine patterns markedly were dependent on the infectious agents, but less so on GBPs.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2020
Keywords
Francisella tularensis, guanylate-binding proteins, mouse co-culture model, cytokine patterns, correlates of protection
National Category
Microbiology in the medical area Immunology
Identifiers
urn:nbn:se:umu:diva-178543 (URN)10.3389/fcimb.2020.594063 (DOI)000601256500001 ()33363054 (PubMedID)2-s2.0-85098192445 (Scopus ID)
Funder
Region Västerbotten, VLL-582571Region Västerbotten, VLL-463691
Available from: 2021-01-14 Created: 2021-01-14 Last updated: 2023-03-23Bibliographically approved
Lindgren, H., Eneslätt, K., Golovliov, I., Gelhaus, C., Rydén, P., Wu, T. & Sjöstedt, A. (2020). Vaccine-Mediated Mechanisms Controlling Francisella tularensis SCHU S4 Growth in a Rat Co-Culture System. Pathogens, 9(5), Article ID 338.
Open this publication in new window or tab >>Vaccine-Mediated Mechanisms Controlling Francisella tularensis SCHU S4 Growth in a Rat Co-Culture System
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2020 (English)In: Pathogens, E-ISSN 2076-0817, Vol. 9, no 5, article id 338Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis causes the severe disease tularemia. In the present study, the aim was to identify correlates of protection in the rat co-culture model by investigating the immune responses using two vaccine candidates conferring distinct degrees of protection in rat and mouse models. The immune responses were characterized by use of splenocytes from naive or Live vaccine strain- (LVS) or clpB/wbtC-immunized Fischer 344 rats as effectors and bone marrow-derived macrophages infected with the highly virulent strain SCHU S4. A complex immune response was elicited, resulting in cytokine secretion, nitric oxide production, and efficient control of the intracellular bacterial growth. Addition of LVS-immune splenocytes elicited a significantly better control of bacterial growth than clpB/wbtC splenocytes. This mirrored the efficacy of the vaccine candidates in the rat model. Lower levels of IFN-gamma, TNF, fractalkine, IL-2, and nitrite were present in the co-cultures with clpB/wbtC splenocytes than in those with splenocytes from LVS-immunized rats. Nitric oxide was found to be a correlate of protection, since the levels inversely correlated to the degree of protection and inhibition of nitric oxide production completely reversed the growth inhibition of SCHU S4. Overall, the results demonstrate that the co-culture assay with rat-derived cells is a suitable model to identify correlates of protection against highly virulent strains of F. tularensis

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
Francisella tularensis, SCHU S4, in vitro co-culture model, rat immune response, correlates of protection, nitrite
National Category
Microbiology in the medical area Immunology
Identifiers
urn:nbn:se:umu:diva-173447 (URN)10.3390/pathogens9050338 (DOI)000541443700021 ()32365846 (PubMedID)2-s2.0-85084201689 (Scopus ID)
Funder
Region Västerbotten, VLL-582571Region Västerbotten, VLL-463691
Available from: 2020-07-10 Created: 2020-07-10 Last updated: 2023-03-24Bibliographically approved
Alam, A., Golovliov, I., Javed, E. & Sjöstedt, A. (2018). ClpB mutants of Francisella tularensis subspecies holarctica and tularensis are defective for type VI secretion and intracellular replication. Scientific Reports, 8, Article ID 11324.
Open this publication in new window or tab >>ClpB mutants of Francisella tularensis subspecies holarctica and tularensis are defective for type VI secretion and intracellular replication
2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 11324Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis, a highly infectious, intracellular bacterium possesses an atypical type VI secretion system (T6SS), which is essential for the virulence of the bacterium. Recent data suggest that the HSP100 family member, ClpB, is involved in T6SS disassembly in the subspecies Francisella novicida. Here, we investigated the role of ClpB for the function of the T6SS and for phenotypic characteristics of the human pathogenic subspecies holarctica and tularensis. The Delta clpB mutants of the human live vaccine strain, LVS, belonging to subspecies holarctica, and the highly virulent SCHU S4 strain, belonging to subspecies tularensis, both showed extreme susceptibility to heat shock and low pH, severely impaired type VI secretion (T6S), and significant, but impaired intracellular replication compared to the wild-type strains. Moreover, they showed essentially intact phagosomal escape. Infection of mice demonstrated that both Delta clpB mutants were highly attenuated, but the SCHU S4 mutant showed more effective replication than the LVS strain. Collectively, our data demonstrate that ClpB performs multiple functions in the F. tularensis subspecies holarctica and tularensis and its function is important for T6S, intracellular replication, and virulence.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-150672 (URN)10.1038/s41598-018-29745-4 (DOI)000439965200017 ()30054549 (PubMedID)2-s2.0-85050803246 (Scopus ID)
Funder
Swedish Research Council, 2013-4581; 2013-8621
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2023-03-24Bibliographically approved
Eneslätt, K., Golovliov, I., Rydén, P. & Sjöstedt, A. (2018). Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system. Frontiers in Cellular and Infection Microbiology, 8, Article ID 27.
Open this publication in new window or tab >>Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system
2018 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 27Article in journal (Refereed) Published
Abstract [en]

Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking. Francisella tularensis is a highly virulent, facultative intracellular bacterium and CMI is critically required for protection against the pathogen, but how this is effectuated in humans is poorly understood. To understand the protective mechanisms, we established an in vitro co-culture assay to identify how control of infection of F. tularensis is accomplished by human cells and hypothesized that the model will mimic in vivo immune mechanisms. Non-adherent peripheral blood mononuclear cells (PBMCs) were expanded with antigen and added to cultures with adherent PBMC infected with the human vaccine strain, LVS, or the highly virulent SCHU S4 strain. Intracellular numbers of F. tularensis was followed for 72 h and secreted and intracellular cytokines were analyzed. Addition of PBMC expanded from naïve individuals, i.e., those with no record of immunization to F. tularensis, generally resulted in little or no control of intracellular bacterial growth, whereas addition of PBMC from a majority of F. tularensis-immune individuals executed static and sometimes cidal effects on intracellular bacteria. Regardless of infecting strain, statistical differences between the two groups were significant, P < 0.05. Secretion of 11 cytokines was analyzed after 72 h of infection and significant differences with regard to secretion of IFN-γ, TNF, and MIP-1β was observed between immune and naïve individuals for LVS-infected cultures. Also, in LVS-infected cultures, CD4 T cells from vaccinees, but not CD8 T cells, showed significantly higher expression of IFN-γ, MIP-1β, TNF, and CD107a than cells from naïve individuals. The co-culture system appears to identify correlates of immunity that are relevant for the understanding of mechanisms of the protective host immunity to F. tularensis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
F. tularensis, in vitro model, human immune response, IFN-gamma, TNF, MIP-1 beta, correlates of immunity
National Category
Microbiology in the medical area Immunology
Identifiers
urn:nbn:se:umu:diva-144645 (URN)10.3389/fcimb.2018.00027 (DOI)000424355900001 ()29468144 (PubMedID)2-s2.0-85041821204 (Scopus ID)
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2023-03-24Bibliographically approved
Wallet, P., Benaoudia, S., Mosnier, A., Lagrange, B., Martin, A., Lindgren, H., . . . Henry, T. (2017). IFN-gamma extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection. PLoS Pathogens, 13(10), Article ID e1006630.
Open this publication in new window or tab >>IFN-gamma extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection
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2017 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, no 10, article id e1006630Article in journal (Refereed) Published
Abstract [en]

Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cellintrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-gamma induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-gamma priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-gamma-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners.

Place, publisher, year, edition, pages
Public Library Science, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-141986 (URN)10.1371/journal.ppat.1006630 (DOI)000414163300008 ()2-s2.0-85031698876 (Scopus ID)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2023-03-24Bibliographically approved
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