TY - JOUR
T1 - Sars-cov-2 induces double-stranded rna-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes
AU - Li, Yize
AU - Renner, David M.
AU - Comar, Courtney E.
AU - Whelan, Jillian N.
AU - Reyes, Hanako M.
AU - Cardenas-Diaz, Fabian Leonardo
AU - Truitt, Rachel
AU - Tan, Li Hui
AU - Dong, Beihua
AU - Alysandratos, Konstantinos Dionysios
AU - Huang, Jessie
AU - Palmer, James N.
AU - Adappa, Nithin D.
AU - Kohanski, Michael A.
AU - Kotton, Darrell N.
AU - Silverman, Robert H.
AU - Yang, Wenli
AU - Morrisey, Edward E.
AU - Cohen, Noam A.
AU - Weiss, Susan R.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Nicholas Parenti for technical help and Dr. Nikki Tanneti for reading the manuscript. This work was supported by NIH Grants AI140442 and supplement for SARS-CoV-2 (to S.R.W.) and AI104887 (to S.R.W. and R.H.S.); funds from the Penn Center for Coronavirus Research and Other Emerging Pathogens (S.R.W. and Y.L.); NIH Grants U01HL148857, R01HL087825, U01HL134745, and R01HL132999 (to E.E.M.); VA administration Grant CX001617 (to N.A.C.); and NIH Grants U01TR001810, N01 75N92020C00005, R01HL095993, and an Evergrande MassCPR award (to D.N.K., J.H., and K.D.A.). R.T. and W.Y. were supported in part by institutional funds from the University of Pennsylvania Perelman School of Medicine to the iPSC Core and by NIH Grant U01TR001810. D.M.R. was supported in part by T32 AI055400 and C.E.C. in part by T32 NS007180.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/4/2
Y1 - 2021/4/2
N2 - 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, OASRNase 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 OASRNase 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.
AB - 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, OASRNase 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 OASRNase 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.
KW - Interferon
KW - Interferon signaling genes
KW - OAS-RNase L
KW - PKR
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85103862253&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103862253&partnerID=8YFLogxK
U2 - 10.1073/PNAS.2022643118
DO - 10.1073/PNAS.2022643118
M3 - Article
C2 - 33811184
AN - SCOPUS:85103862253
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 16
M1 - e2022643118
ER -