Influenza A virus modulates ACE2 expression and SARS-CoV-2 infectivity in human cardiomyocytes
Qian Wu,
Naresh Kumar,
William P. Lafuse,
Omar Santiagonunez Ahumada,
Noushin Saljoughian,
Elizabeth Whetstone,
Ashley Zani,
Ashley K. Patton,
Mona El Refaey,
Amy Webb,
Maciej Pietrzak,
Lianbo Yu,
Mahesh KC,
Mark E. Peeples,
Latha P. Ganesan,
Jacob S. Yount,
Murugesan V.S. Rajaram
Affiliations
Qian Wu
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Naresh Kumar
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
William P. Lafuse
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Omar Santiagonunez Ahumada
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Noushin Saljoughian
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Elizabeth Whetstone
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Ashley Zani
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Ashley K. Patton
Department of Pathology, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Mona El Refaey
Department of Surgery, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Amy Webb
Department of Biomedical Informatics, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Maciej Pietrzak
Department of Biomedical Informatics, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Lianbo Yu
Department of Biomedical Informatics, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Mahesh KC
Department of Pediatrics, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA; Center for Vaccines and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Mark E. Peeples
Department of Pediatrics, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA; Center for Vaccines and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Latha P. Ganesan
Department of Internal Medicine College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA
Jacob S. Yount
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA
Murugesan V.S. Rajaram
Department of Microbial Infection and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43209, USA; Corresponding author
Summary: Influenza A virus (IAV) and SARS-CoV-2 virus are both acute respiratory viruses currently circulating in the human population. This study aims to determine the impact of IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. Infection of human bronchial epithelial cells (HBEC), A549 cells, lung fibroblasts (HLF), monocyte derived macrophages (MDMs), cardiac fibroblasts (HCF) and hiPSC-derived cardiomyocytes with IAV enhanced the expression of ACE2, the SARS-CoV-2 receptor. Similarly, IAV infection increased levels of ACE2 in the lungs of mice and humans. Of interest, we detected heavily glycosylated form of ACE2 in hiPSC-CMs and poorly glycosylated ACE2 in other cell types. Also, prior IAV infection enhances SARS-CoV-2 spike protein binding and viral entry in all cell types. However, efficient SARS-CoV-2 replication was uniquely inhibited in cardiomyocytes. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Ang II, induction of eNOS and nitric oxide production, may provide a potential mechanism for the restricted SARS-CoV-2 replication in cardiomyocytes.
