Mechanistic elucidation of inflammasome assembly and regulation. Supplement: Testing drugs that curtail inflammasome activation to suppress SARS-CoV-2 pathogenesis

Abstract Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1b and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no structural and mechanistic information is available. This proposal seeks to link SARS-CoV-2 infection to inflammasomes and to test whether inflammasome inhibitors alleviate SARS-CoV-2 pathogenesis. Inflammasome activation, in particular through the NLRP3 inflammasome and the pore forming protein GSDMD, underlies the serious, and often fatal cytokine storm, lung inflammation and sepsis that are associated with SARS-CoV-2 clinical deterioration. It may even contribute to lymphopenia, an important characteristic of severe COVID-19 cases. These data from SARS-CoV-2 and from related coronaviruses, SARS-CoV and MERS-CoV, led us to propose the following hypothesis: the severe acute respiratory syndrome (SARS) pneumonia induced by SARS-CoV-2 is caused by massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine responses that depend on GSDMD and/or NLRP3 activation.