Influenza A virus modulates ACE2 expression and SARS-CoV-2 infectivity in human cardiomyocytes

Abstract

Abstract Influenza A virus (IAV) and SARS-CoV-2 are both acute respiratory viruses currently circulating in the human population. Prior IAV infection enhances SARS-CoV-2 infectivity and lung pathogenesis in mice; however, underlying mechanisms and the extent that co-infection leads to involvement of other organs in disease severity remains unknown. Herein, we investigated the impact of prior IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. IAV infection induces the expression of ACE2 in human lung epithelial cells, lung fibroblasts, macrophages, cardiac fibroblasts (HCFs), and hiPSC-Cardiomyocytes (CMs). Interestingly, we detected poorly glycosylated ACE2 in lung epithelial cells and cardiac fibroblasts. In contrast, expression of a heavily glycosylated form of ACE2 is induced by IAV in CMs. In all cell types, IAV infection enhances SARS-CoV-2 viral entry. However, efficient SARS-CoV-2 replication was uniquely inhibited in CMs. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Angiotension II, induction of eNOS and nitric oxide production, providing a mechanistic underpinning for restricted viral replication in CMs. Our results indicate that IAV-mediated induction of ACE2 is double-edged, providing increased risk for SARS-CoV-2 coinfection in epithelial cells and HCFs, while limiting SARS-CoV-2 replication in CMs. We conclude that differential glycosylation of ACE2 may be a molecular determinant, not of SARS-CoV-2 infection, but of replication. Funding: NIH grants R01-AI 146252, R21-AI 146690 Funding: NIH grants R01-AI 146252, R21-AI 146690