Bacterial modulation of noncanonical inflammasome.

Abstract

Abstract Sensing of microbial products by pattern recognition receptors to mount effective antimicrobial responses is an evolutionarily conserved immune strategy. Cytosolic LPS sensing by the noncanonical inflammasome via caspase-11 and the ensuing IL-1 and cell death responses are emerging as a key host defense strategy that play a crucial role in the clearance of infectious agents. A strong selection pressure from the host such as this drives pathogens to develop strategies to actively antagonize or evade inflammasome responses. However, it is not known if bacteria antagonize noncanonical inflammasome pathway. This study addresses this knowledge gap and examines the modulation of noncanonical inflammasome by bacteria utilizing Enterohemorrhagic E. coli (EHEC) as a model organism. Supporting the idea of inflammasome suppression by EHEC, our results indicate that compared to E. coli K12, an avirulent laboratory strain of E. coli, EHEC induces substantially weaker cell death and IL-1 secretion. Importantly, by screening a library of EHEC mutants lacking known and putative virulence factors, we found that a mutant that lacks an EHEC-specific genomic island triggered markedly higher cell death and IL-1 responses compared to wild-type EHEC revealing that this genomic island harbors a suppressor of noncanonical inflammasome. Altogether, this study attributes an inflammasome modulatory function to an EHEC genomic island, whose function was previously unknown. Identifying novel mechanisms by which pathogenic bacteria silence noncanonical inflammasome is crucial as it may aid in designing novel therapeutic approaches against Gram-negative infections.