Bacterial modulation of noncanonical inflammasome

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Project Summary/Abstract During host-bacterial pathogen encounters, the host cells are exposed to an array of microbial components, including virulence factors such as bacterial toxins and pathogen- associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and flagellin. The innate immune system employs germline-encoded pattern recognition receptors to survey the extra- and intra-cellular milieu for the presence of PAMPs and mount appropriate defense responses. Concurrently, bacterial virulence factors directly induce and/or rewire cellular processes that favor bacterial colonization with or without tissue damage. The crosstalk between the PAMP-induced innate immune responses and virulence factor-induced cellular responses are vital determinants of the fate of host-pathogen interactions. Therefore, an in-depth understanding of these interactions is critical for gaining insights into the mechanisms of bacterial diseases. However, these interactions are poorly characterized in several bacterial infections. This project will address this knowledge gap utilizing a human pathogen, Enterohemorrhagic Escherichia coli (EHEC), the causative agent of hemorrhagic colitis and hemolytic uremic syndrome (HUS). During EHEC infection, host cells encounter bacterial factors, including Shiga toxin, type III secretion system components, and LPS. A unique noncanonical inflammasome pathway senses EHEC LPS entering host cell cytosol via outer membrane vesicles; cytosolic LPS binds and activates an inflammatory caspase, caspase-11, which then mediates cell death, caspase-1 activation, and downstream IL-1 cytokine production. The studies proposed in three specific aims will systematically characterize how an EHEC virulence factor subverts the noncanonical inflammasome-mediated host responses and how the noncanonical inflammasome reciprocally regulate EHEC disease pathogenesis in a clinically relevant murine model of EHEC infection. Thus, the findings from this study provides critical molecular and cellular insights into a complex interplay between a classic bacterial PAMP- and virulence factor-induced host signaling pathways and its impact on disease pathogenesis in a clinically relevant infection.