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

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. © 2010 carlsson et al.