Host-Detrimental Role of Esx-1-Mediated Inflammasome Activation in Mycobacterial Infection

PLoS Pathogens

Kai H. Barck¹  Richard A. D. Carano¹  Eric J. Brown²  Fredric Carlsson²  Lauri Diehl³  Mei Sun³  Janice Kim⁴  Calin Dumitru⁴ 

[1] Department of Biomedical Imaging, Genentech Inc., South San Francisco, California, United States of America;Department of Microbial Pathogenesis, Genentech Inc., South San Francisco, California, United States of America;Department of Pathology, Genentech Inc., South San Francisco, California, United States of America;Department of Translational Immunology, Genentech Inc., South San Francisco, California, United States of America

关键词: Macrophages;    Inflammasomes;    Mycobacterium tuberculosis;    Granulomas;    Cytokines;    Secretion;    T cells;    Bacterial growth;   

DOI  :  10.1371/journal.ppat.1000895

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-1β, 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.

【 授权许可】

CC BY