Proc Natl Acad Sci U S A . SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes

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Proc Natl Acad Sci U S A


. 2021 Apr 20;118(16):e2022643118.
doi: 10.1073/pnas.2022643118.
SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes


Yize Li ^{1 2} , David M Renner ^{3 2} , Courtney E Comar ^{3 2} , Jillian N Whelan ^{3 2} , Hanako M Reyes ^{3 2} , Fabian Leonardo Cardenas-Diaz ^{4 5} , Rachel Truitt ^{4 6} , Li Hui Tan ⁷ , Beihua Dong ⁸ , Konstantinos Dionysios Alysandratos ⁹ , Jessie Huang ⁹ , James N Palmer ⁷ , Nithin D Adappa ⁷ , Michael A Kohanski ⁷ , Darrell N Kotton ⁹ , Robert H Silverman ⁸ , Wenli Yang ⁴ , Edward E Morrisey ^{4 5} , Noam A Cohen ^{7 10 11} , Susan R Weiss ^{1 2}



Affiliations

• PMID: 33811184
• DOI: 10.1073/pnas.2022643118

Abstract

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.

Keywords: OAS-RNase L; PKR; SARS-CoV-2; interferon; interferon signaling genes.