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-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.

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

“…We hypothesize that ESX-1 affects both inflammasome activation and onset of cell death indirectly through lysosomal rupture, translocation, and concomitant release of cathepsin B, whereas ESX-5 substrates influence these processes probably more directly through a cytosolic mechanism. We have observed that M. marinum further induced inflammasome activation through the generation of ROS and KCl efflux, suggesting involvement of NLRP3 inflammasome, which was recently also demonstrated by Carlsson et al (15).…”

“…By contrast, in this study we have observed that the ESX-5 mutant also affects inflammasome activation, whereas secretion of ESAT-6 and translocation into the cytosol are unaffected. As inflammasome activation upon infection with M. marinum is reported to exacerbate disease without affecting bacterial growth (15), ESX-5 activation of inflammasomes is most likely beneficial for the bacterium. Therefore, we can conclude that ESX-1 and ESX-5 play distinct roles in inflammasome activation.…”

“…Inflammasome activation upon M. marinum infection can exacerbate disease (42) indicating a host-detrimental and bacterium-promoting role of the inflammatory pathway during mycobacterial infection (15). Previous studies demonstrated that infection of macrophages with pathogenic mycobacteria results in the induction of IL-1b release, which is dependent on both ESX-1 and ESX-5 (7,(13)(14)(15). Fig.…”

“…Caspase-1 itself needs activation by inflammasomes, protein complexes that sense cytosolic bacterial products and endogenous danger signals. Both M. tuberculosis and M. marinum reportedly induce IL-1b secretion through NALP3 inflammasomes in an ESX-1-dependent manner (13)(14)(15)(16). Recently, we observed that ESX-5 is also required for IL-1b secretion upon infection with M. marinum (7).…”

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

“…The NLRP3 inflammasome is activated by bacteria expressing pore-forming toxins or secretion systems (18)(19)(20)(21)(22)(23). Moreover, it can be stimulated by necrotic cells and endogenous danger-associated molecules such as uric acid crystals and ATP, as well as by silica crystals, asbestos, and aluminum salts (21,(24)(25)(26)(27)(28)(29)(30).…”