PROJECT 1 - ABSTRACT The rapid development of SARS-CoV-2 vaccines has helped ease most of the restrictions in place during the height of the pandemic to limit transmission of the virus. Unfortunately, the adaptive immunity (i.e., antibody and T cell responses) induced by current vaccines declines rapidly, thus requiring frequent boosts. Most importantly, current vaccines fail to optimally protect against emerging SARS-CoV-2 variants of concern (VOCs). The clinical manifestations of SARS-CoV-2 infections are highly variable, and patients can be asymptomatic or exhibit symptoms ranging from mild, moderate, or severe conditions that can lead to death. It is estimated that over 30% of SARS-CoV-2 infected people worldwide (~ 65 millions) have developed Post-Acute COVID Syndrome (PACS), or Long COVID, characterized by pulmonary, mental health, neurological, hematological, diabetes, gastrointestinal, kidney, musculoskeletal, and cardiovascular disorders. Prior infections do not eliminate risks of PACS, and 10-12% of cases are after breakthrough SARS-CoV-2 infection in vaccinated individuals Furthermore, reinfections were recently reported to increase the risks of death, hospitalization and PACS. Thus, new therapeutic approaches are needed to prevent or better manage acute SARS-CoV-2 infections and PACS. COVID-19 patients exhibit excessive inflammatory responses and the release of a large amount of pro- inflammatory cytokines, or cytokine storm which directly correlate with lung injury, multiple organ failure, and an unfavorable prognosis. We recently observed that human caspase-4 (CASP4), which is a homolog of mouse CASP11, is significantly upregulated in nasal swabs and lungs of patients with severe SARS-CoV-2 disease. Furthermore, we found that mice lacking CASP11 develop less severe disease after infection with SARS-CoV-2 and we reported that CASP11 mediates lung pathology, inflammation, and thrombosis during SARS-CoV-2 infection. This project aims to elucidate immune check points regulated by CASP11 during mild, severe COVID- 19 and PACS. We will also test whether targeting CASP11 alone of together with factors which regulate viral replication during severe SARS-CoV-2 could improve/prevent pathologies and enhance/promote protective adaptive immunity.