Cutting Edge: Mycobacterium tuberculosis but Not Nonvirulent Mycobacteria Inhibits IFN-β and AIM2 Inflammasome–Dependent IL-1β Production via Its ESX-1 Secretion System

Abstract

Mycobacterium tuberculosis (Mtb) extracellular DNA (eDNA) gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this eDNA of Mtb does not induce activation of the AIM2-inflammasome since AIM2 recognizes cytosolic DNA. Here we show that non-virulent mycobacteria such as M. smegmatis induce AIM2-inflammasome activation, which is dependent upon their strong induction of IFN-β production. In contrast, Mtb, but not an ESX-1 deficient mutant, inhibits the AIM2-inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that Mtb inhibits IFN-β production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of Mtb that involves the ESX-1-dependent, direct or indirect, suppression of the host cell AIM2-inflammasome activation during infection.

Evasion of inflammasome activation by microbial pathogens

“…Interestingly, the DNA that enters the host cell does not result in AIM2 inflammasome activation. ESX-1-competent M. tuberculosis, but not other closely related species of Mycobacterium, inhibits secretion of IFN-β by host cells as well as IFN-β-mediated signaling (53). This M. tuberculosis-mediated reduction in IFN-β secretion was partially responsible for the ability of M. tuberculosis to inhibit AIM2 inflammasome activation, as type I IFN signaling is required for AIM2 inflammasome activation (54).…”

Autophagy in the Fight Against Tuberculosis

“…For instance, autophagy seems to positively regulate the expression and secretion of TNF-a (Crisan et al, 2011;Jo, 2013) and to negatively regulate the secretion of several other proinflammatory cytokines, including IL-1a, IL-1b, and IL-18 (Saitoh et al, 2008;Crisan et al, 2011;Harris et al, 2011;Nakahira et al, 2011;Zhou et al, 2011;Jo, 2013). For the specific case of IL-1b, autophagy was shown to control its expression by different ways: increasing degradation of pro-IL-1b and inhibiting AIM2 and NLRP3 inflammasomes, which decrease IL-1b processing and secretion Nakahira et al, 2011;Zhou et al, 2011;Bradfute et al, 2013;Shah et al, 2013). Although IL-1 is necessary for protection against mycobacteria, negative regulation of IL-1 by autophagy is likely to have beneficial effects to the infected cells as high levels of IL-1 are associated with excessive inflammation and pathology, suggesting that a precise control of IL-1 expression and release is needed for a successful response against infection (Bradfute et al, 2013).…”

Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens

“…Similarly, subversion of Nlrc4-and Nlrp3-dependent detection of Salmonella requires bacterial oxidative phosphorylation genes such as aconitase (acnB), isocitrate dehydrogenase (icdA) and isocitrate lyase (aceA) [26 ]. Mtb subverts Aim2 and Nlrp3 inflammasomes in mouse cells in a T7SS dependent manner [27].…”