Mechanisms of inflammasome activation and inhibition during Yersinia infection

Abstract

The host inflammatory response is strikingly delayed during the initial stages of infection with Yersinia pestis and Y. pseudotuberculosis, pathogens that can suppress immune defenses. This work identifies the bacterial leucine-rich repeat protein YopM as an inhibitor of pyroptosis, an inflammatory programmed cell death pathway. Pyroptosis, which depends on the protease caspase-1, restricts Yersinia infection. Consequently, YopM subversion of caspase-1 is essential for bacterial virulence. Caspase-1 is activated after a multistep process of inflammasome formation, and YopM is bifunctional in preempting pyroptosis: it blocks caspase-1 recruitment to pre-inflammasome complexes and directly inhibits caspase-1 proteolysis. These data highlight the importance of caspase-1 in combating microbial infection and indicate that Yersinia are highly susceptible to pyroptosis, but normally prevent caspase-1 activation with YopM. Though Yersinia pestis actively antagonizes inflammasome formation to delay inflammatory processes, Yersinia PAMPs are rapidly recognized by NLRs during infection. This work shows that the Yersinia insecticidal-like toxin complex (YTc) activates the inflammasome and is a predominant PAMP of Y. pestis. YTc forms pores in the phagolysosome membrane that activate the NLRP3 inflammasome. These pores result in release of Cathepsin B, ROS, and protons, but only Cathepsin B is responsible for inflammasome formation. Thus it appears that YTc-mediated intracellular survival comes with the liability of stimulating an inflammatory anti-microbial response that is detrimental to Yersinia survival. Together, these results describe previously unknown functions of YopM and YTc contributing to the virulence of Yersinia.