Inflammasomes recruit natural killer cells to prevent infection by a ubiquitous environmental bacterium (MPF4P.726)

Abstract

Abstract Our lab has shown that inflammasome-triggered pyroptosis ejects microbes from replication niches in macrophages, exposing them to neutrophil killing. Because bona fide intracellular pathogens must evade pyroptosis in vivo, the role of pyroptosis in defense has primarily been observed in pathogens deprived of evasion strategies. To identify naturally occurring bacteria that are cleared via pyroptosis, we considered pathogens that are specific to chronic granulomatous disease (CGD), a neutrophil killing deficiency. We hypothesize that a subset of these microbes may be detected by inflammasomes and cleared via pyroptosis. In a survey of CGD pathogens, we discovered a ubiquitous environmental microbe, Chromobacterium violaceum, that is avirulent in WT mice (which resist a 1,000,000 CFU challenge), but is extremely virulent in inflammasome deficient mice (succumb to 100 CFU). This is the most penetrant inflammasome phenotype against any infection: bacterial, viral, fungal, or parasitic. Further, our studies with C. violaceum reveal a unique link between inflammasome driven IL-18 and NK cell cytotoxicity that functions in parallel to pyroptosis to eliminate intracellular replication niches. We posit that a subset of environmental microbes can be developed as powerful in vivo tools to study innate immune responses in the context of an appropriate and fully functional inflammasome response.