Overriding the Immune Evasion Tactics of Coronavirus

PROJECT SUMMARY/ABSTRACTProgression of SARS-Coronavirus-2 (SARS-CoV-2) infected patients to life threatening disease may result froma virus-mediated, dysregulated immune response associated with excessive production of inflammatorycytokines, cytokine release syndrome. In this proposal we seek to identify therapeutics and knowledge ofCoronaviruses that will counteract the disruption in cytokine signaling pathways involved in effective hostdefense. We contribute to the urgent need for therapeutics that inhibit SARS-CoV-2 infection using pathwayspecific reporter cells to screen for therapeutically active compounds that restore cytokine signaling. Our pathwayspecific screens are a component in SBP-wide initiative to develop therapeutics that limit severe COVID-19. Ourscreening strategy selects drugs identified in libraries of pharmacologically active therapeutics that block SARS-CoV-2 lytic replication. We use cytokine pathway reporters to test these compounds in SARS-CoV-2 infection ofa lung cell line and human lung organoids in BSL3 facilities. The selected candidates will undergo analysis forpotential drug development. Fundamental knowledge of cytokine-regulated defense mechanisms related to Coronavirus infectionlimits the rational design of therapeutics and vaccines. To advance this knowledge we focus on the Lymphotoxin-β Receptor (LTβR) and the Herpesvirus entry mediator (HVEM, TNFRSF14) pathways known to regulate anti-viral cytokines, interferons (IFN) and interleukin-1(IL1β). Together, the LTβR and HVEM pathways act as anintegrated, homeostatic network that inhibits virus replication yet limits tissue damaging cytokines. Two SARS-CoV-2 proteins, the Papain-like protease (PLPro, Nsp3) and Nsp9 target novel components in the TRAF3interactome that control the NFκB transcriptome. We will determine the role of these components in the keycytokine pathways using genetic and pharmacologic approaches in a mouse coronavirus lung infection model.Together these two independent but complementary aims will provide an opportunity to help solve the SARS-CoV-2 pandemic, and protect future generations.