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

AbstractInflammasomes are supramolecular signaling complexes that activate a subset of caspasesknown as inflammatory caspases such as caspase-1. Upon stimulation by microbial anddamage-associated signals, inflammasomes assemble to elicit the first line of host defense byproteolytic 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 downstreameffector, and in most cases an adaptor molecule such as apoptosis-associate speck-like proteincontaining a caspase recruitment domain (ASC). Depending on whether ASC is required,inflammasomes can be categorized into ASC-dependent and ASC-independentinflammasomes. Despite the biological importance of inflammasomes in innate immunity, nostructural and mechanistic information is available.This proposal seeks to link SARS-CoV-2 infection to inflammasomes and to test whetherinflammasome inhibitors alleviate SARS-CoV-2 pathogenesis. Inflammasome activation, inparticular through the NLRP3 inflammasome and the pore forming protein GSDMD, underliesthe serious, and often fatal cytokine storm, lung inflammation and sepsis that are associatedwith SARS-CoV-2 clinical deterioration. It may even contribute to lymphopenia, an importantcharacteristic of severe COVID-19 cases. These data from SARS-CoV-2 and from relatedcoronaviruses, SARS-CoV and MERS-CoV, led us to propose the following hypothesis: thesevere acute respiratory syndrome (SARS) pneumonia induced by SARS-CoV-2 is caused bymassive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokineresponses that depend on GSDMD and/or NLRP3 activation.