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

Autor:	Li Y; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; weisssr@pennmedicine.upenn.edu yizelee@gmail.com.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Renner DM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Comar CE; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Whelan JN; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Reyes HM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Cardenas-Diaz FL; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Truitt R; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Tan LH; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Dong B; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Alysandratos KD; Department of Medicine, The Pulmonary Center, Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA 02118., Huang J; Department of Medicine, The Pulmonary Center, Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA 02118., Palmer JN; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Adappa ND; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Kohanski MA; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Kotton DN; Department of Medicine, The Pulmonary Center, Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA 02118., Silverman RH; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Yang W; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Morrisey EE; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Penn-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104., Cohen NA; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.; Division of Otolaryngology, Department of Surgery, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104.; Monell Chemical Senses Center, Philadelphia, PA 19104., Weiss SR; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; weisssr@pennmedicine.upenn.edu yizelee@gmail.com.; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Apr 20; Vol. 118 (16).
DOI:	10.1073/pnas.2022643118
Abstrakt:	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 A549 ACE2 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 A549 ACE2 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 A549 ACE2 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. Competing Interests: Competing interest statement: S.R.W. is on the scientific advisory board of Immunome, Inc. and Ocugen, Inc. R.H.S. is a consultant to Cutherna, Inc. (Copyright © 2021 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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