tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], David M Renner[SUP] 3 2 [/SUP], Courtney E Comar[SUP] 3 2 [/SUP], Jillian N Whelan[SUP] 3 2 [/SUP], Hanako M Reyes[SUP] 3 2 [/SUP], Fabian Leonardo Cardenas-Diaz[SUP] 4 5 [/SUP], Rachel Truitt[SUP] 4 6 [/SUP], Li Hui Tan[SUP] 7 [/SUP], Beihua Dong[SUP] 8 [/SUP], Konstantinos Dionysios Alysandratos[SUP] 9 [/SUP], Jessie Huang[SUP] 9 [/SUP], James N Palmer[SUP] 7 [/SUP], Nithin D Adappa[SUP] 7 [/SUP], Michael A Kohanski[SUP] 7 [/SUP], Darrell N Kotton[SUP] 9 [/SUP], Robert H Silverman[SUP] 8 [/SUP], Wenli Yang[SUP] 4 [/SUP], Edward E Morrisey[SUP] 4 5 [/SUP], Noam A Cohen[SUP] 7 10 11 [/SUP], Susan R Weiss[SUP] 1 2 [/SUP]
Affiliations
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[SUP]ACE2[/SUP] 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[SUP]ACE2[/SUP] 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[SUP]ACE2[/SUP] 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.
. 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[SUP] 1 2 [/SUP], David M Renner[SUP] 3 2 [/SUP], Courtney E Comar[SUP] 3 2 [/SUP], Jillian N Whelan[SUP] 3 2 [/SUP], Hanako M Reyes[SUP] 3 2 [/SUP], Fabian Leonardo Cardenas-Diaz[SUP] 4 5 [/SUP], Rachel Truitt[SUP] 4 6 [/SUP], Li Hui Tan[SUP] 7 [/SUP], Beihua Dong[SUP] 8 [/SUP], Konstantinos Dionysios Alysandratos[SUP] 9 [/SUP], Jessie Huang[SUP] 9 [/SUP], James N Palmer[SUP] 7 [/SUP], Nithin D Adappa[SUP] 7 [/SUP], Michael A Kohanski[SUP] 7 [/SUP], Darrell N Kotton[SUP] 9 [/SUP], Robert H Silverman[SUP] 8 [/SUP], Wenli Yang[SUP] 4 [/SUP], Edward E Morrisey[SUP] 4 5 [/SUP], Noam A Cohen[SUP] 7 10 11 [/SUP], Susan R Weiss[SUP] 1 2 [/SUP]
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[SUP]ACE2[/SUP] 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[SUP]ACE2[/SUP] 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[SUP]ACE2[/SUP] 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.