Mechanisms of lung and cardiac pathology in SARS-CoV-2 infections

SUMMARY This project aims to mechanistically understand and combat pathological mechanisms activated by SARS- CoV-2 in the lungs and heart. We will further investigate whether these mechanisms are altered in specific immunodeficiencies linked to severe COVID-19. Our work will leverage major discoveries made by our group, including that the non-canonical inflammasome protein Caspase-11 (CASP11, homologous to CASP4 in humans) promotes pathological inflammation in SARS-CoV-2 infection, and that CASP11 KO mice experience significantly less severe infections than than WT mice. In Aim 1, we will test the hypothesis that cell-specific roles of CASP11 mediate SARS-CoV-2 pathogenesis by examining infections of cell-specific CASP11 KO mice (CASP11 flox allele mice). Further, we will target CASP11 downstream effectors identified by our work, such as the chemokine CXCL1 and recruited neutrophils, to determine their roles in unique aspects of SARS-CoV-2 pathogenesis. We will examine additional emergent candidate CASP11-dependent molecules, using genetic, neutralizing antibody, and chemical inhibitor strategies. This aim will yield new understanding of roles for CASP11 in specific cell types and will identify tailored strategies for preventing or treating unique aspects of COVID-19 pathology. In Aim 2, we will test the hypothesis that CASP11-dependent mechanisms of pathogenesis are exacerbated in specific immunodeficiencies linked to severe COVID-19. These include type I interferon (IFN) and IFN-induced transmembrane protein 3 (IFITM3) deficiencies. We have shown IFN alpha receptor KO and IFITM3 KO mice model these deficiencies, including exacerbated lung infections and virus dissemination to the heart. The use of these models in combination with CASP11 KOs will allow identification of pathogenic mechanisms in the lungs, and in the hearts of mice with or without direct cardiac tissue infection. Overall, our work will reveal fundamental mechanisms of SARS-CoV-2 pathogenesis in the lungs and heart, including involvement of specific cell types, pathways, and molecules, thus revealing targetable therapeutic strategies for combating COVID-19 in immunocompetent, as well as highly vulnerable, populations.