title: Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection.
abstract: The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1beta, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome.
authors.affiliation: Department of Microbial Pathogenesis, Genentech Inc., South San Francisco, California, USA. fredric.carlsson@ki.se
authors.forename: Fredric
authors.initials: F
authors.lastname: Carlsson
authors.forename: Janice
authors.initials: J
authors.lastname: Kim
authors.forename: Calin
authors.initials: C
authors.lastname: Dumitru
authors.forename: Kai H
authors.initials: KH
authors.lastname: Barck
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010588:Phagosomes / Q000276:immunology; D013623:Tail / Q000382:microbiology; D014375:Tuberculoma / Q000276:immunology / Q000382:microbiology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D037521:Virulence Factors
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