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 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.
Highlights
Much of their genomes, including their ∼20-kb Orf1ab conserved replicase locus, to encode proteins that antagonize host cell responses [3]
While early innate immune responses are essential for protection against virus invasion and inadequate responses are associated with severe COVID-19 disease, gaps remain in our knowledge about the interaction of SARS-CoV-2 with host antiviral pathways
Middle East respiratory syndrome (MERS)-CoV replication peaked at 96 hpi, at a lower titer than SARS-CoV-2, and produced fewer plaque-forming units (PFU) per milliliter at later time points
Summary
Much of their genomes, including their ∼20-kb Orf1ab conserved replicase locus, to encode proteins that antagonize host cell responses [3]. We characterized the innate immune response to SARS-CoV-2 in relevant respiratory tractderived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase– ribonuclease L and protein kinase R, while inducing minimal levels of interferon. This is in contrast to Middle East respiratory syndrome-CoV, which inhibits all three pathways. SARS-CoV-2 emerged in China in late 2019, causing the COVID-19 pandemic with extensive morbidity and mortality, leading to major changes in day-to-day life in many parts of the world This was the third lethal respiratory human coronavirus— after SARS-CoV in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012—to emerge from bats in the 21st century. It is important to understand how these viruses interact with their host
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