SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 16; pp. 1 - 11
• Main Authors: Li, Yize, Renner, David M., Comar, Courtney E., Whelan, Jillian N., Reyes, Hanako M., Cardenas-Diaz, Fabian Leonardo, Truitt, Rachel, Tan, Li Hui, Dong, Beihua, Alysandratos, Konstantinos Dionysios, Huang, Jessie, Palmer, James N., Adappa, Nithin D., Kohanski, Michael A., Kotton, Darrell N., Silverman, Robert H., Yang, Wenli, Morrisey, Edward E., Cohen, Noam A., Weiss, Susan R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.04.2021
• Subjects: A549 Cells; Alveoli; Antagonists; Biological Sciences; Cardiomyocytes; Cell activation; Cell lines; Coronaviridae; Coronaviruses; COVID-19; Double-stranded RNA; eIF-2 Kinase; Endoribonucleases - metabolism; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - virology; Epithelium; Humans; Immune response; Immunity, Innate; Infections; Innate immunity; Interferon; Kinases; Lung - pathology; Lungs; Middle East respiratory syndrome; Middle East Respiratory Syndrome Coronavirus - immunology; Middle East Respiratory Syndrome Coronavirus - physiology; Myocytes, Cardiac - immunology; Myocytes, Cardiac - virology; Nose - virology; Pathogenesis; Pluripotency; Protein kinase R; Respiratory diseases; Ribonuclease L; RNA, Double-Stranded - metabolism; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Signaling; Stem cells; Viral diseases; Virus Replication; Viruses; interferon signaling genes; SARS-CoV-2; OAS-RNase L; interferon; PKR
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2022643118

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2–infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host–virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.