Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection

PLoS Pathog. 2010 May 6;6(5):e1000895. doi: 10.1371/journal.ppat.1000895.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Bacterial Proteins / metabolism
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Host-Pathogen Interactions / immunology*
  • Inflammation / immunology
  • Inflammation / microbiology
  • Interleukin-1beta / metabolism
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium Infections, Nontuberculous / immunology*
  • Mycobacterium Infections, Nontuberculous / microbiology
  • Mycobacterium marinum / growth & development*
  • Mycobacterium marinum / immunology
  • Mycobacterium marinum / pathogenicity
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phagosomes / immunology
  • Tail / microbiology
  • Tuberculoma / immunology
  • Tuberculoma / microbiology
  • Virulence
  • Virulence Factors / genetics
  • Virulence Factors / immunology
  • Virulence Factors / metabolism


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Virulence Factors