Mechanisms of Inflammasome Defense against Cytosol-invasive Bacteria

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Abstract Inflammasomes survey the cytosol for signs of perturbation or bacterial contamination and initiate inflammation during microbial defense or inflammatory diseases. The NLRC4 inflammasome detects the activity of bacterial type III secretion systems (T3SS) as well as flagellin, and then activates caspase-1, which processes IL-1β and IL-18 to their mature forms, and initiates a form of programmed lytic cell death called pyroptosis to prevent the establishment of an intracellular replication niche. Caspase-11, the non-canonical inflammasome, detects LPS in the cytosol and triggers pyroptosis, but cannot process pro-IL-1β or IL-18 alone. Using Burkholderia thailandensis, a model for the cytosol invasive select agent Burkholderia pseudomallei, I found that B. thailandensis is primarily cleared via caspase-11, while caspase-1 plays a minor role in defense. Specifically, I found that caspase-1 activation by the T3SS provides a priming signal, IL-18-induced IFN-γ, upstream of caspase-11 expression during defense against B. thailandensis, leading to clearance in 24 hours. By contrast, in the absence of caspase-1-driven IL-18, bacterial burdens persist for several days, eventually triggering other signals that induce IFN-γ and downstream caspase-11 expression. In this proposal, I will investigate why caspase-1 and -11 dependent pyroptosis are not equivalent, and what is the cellular source of IFN-γ that prime caspase-11 to protect against B.thailandensis. These studies will provide new insights into the mechanisms behind inflammasome-mediated defense against infection, and thus aid future treatments aimed at therapeutic manipulation of the host innate immune system.