{"doi":"10.1073/pnas.2022643118","title":"SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes","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.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":146176,"datarank":0.8294143631267137,"base_score":5.529429087511423,"endowment":5.529429087511423,"self_citation_contribution":0.8294143631267137,"citation_network_contribution":0.0,"self_endowment_contribution":0.8294143631267137,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":251,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":621041,"name":"David M. 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Alysandratos","orcid":null,"position":9,"is_corresponding":false},{"id":232288,"name":"Jessie Huang","orcid":"0000-0002-5297-3563","position":10,"is_corresponding":false},{"id":232128,"name":"Nithin D. Adappa","orcid":"0000-0002-7535-9339","position":11,"is_corresponding":false},{"id":264133,"name":"Michael A. Kohanski","orcid":"0000-0001-8399-364X","position":13,"is_corresponding":false},{"id":228731,"name":"Darrell N. Kotton","orcid":"0000-0002-9604-8476","position":14,"is_corresponding":false},{"id":301338,"name":"Robert H. Silverman","orcid":"0000-0003-2432-992X","position":15,"is_corresponding":false},{"id":570697,"name":"Wenli Yang","orcid":"0000-0002-1873-2336","position":16,"is_corresponding":false},{"id":228733,"name":"Edward E. Morrisey","orcid":"0000-0001-5785-1939","position":17,"is_corresponding":false},{"id":264137,"name":"Noam A. Cohen","orcid":"0000-0002-9462-3932","position":18,"is_corresponding":false},{"id":456973,"name":"Susan R. 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