{"doi":"10.1101/2023.02.28.530557","title":"Type I interferon signaling induces a delayed antiproliferative response in Calu-3 cells during SARS-CoV-2 infection","abstract":"ABSTRACT Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases of COVID-19 characterized by direct injury of the alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory epithelial cell death and proliferation during SARS-CoV-2 infection, however, remain poorly understood. We now report a high-throughput CRISPR screen for host genetic modifiers of the survival and proliferation of SARS-CoV-2-infected Calu-3 respiratory epithelial cells. The top 4 genes identified in our screen encode components of the same type I interferon signaling complex – IFNAR1 , IFNAR2 , JAK1 , and TYK2 . The 5 th gene, ACE2 , was an expected control encoding the SARS-CoV-2 viral receptor. Surprisingly, despite the antiviral properties of IFN-I signaling, its disruption in our screen was associated with an increase in Calu-3 cell fitness. We validated this effect and found that IFN-I signaling did not sensitize SARS-CoV-2-infected cultures to cell death but rather inhibited the proliferation of surviving cells after the early peak of viral replication and cytopathic effect. We also found that IFN-I signaling alone, in the absence of viral infection, was sufficient to induce this delayed antiproliferative response. Together, these findings highlight a cell autonomous antiproliferative response by respiratory epithelial cells to persistent IFN-I signaling during SARS-CoV-2 infection. This response may contribute to the deficient alveolar regeneration that has been associated with COVID-19 lung injury and represents a promising area for host-targeted therapeutic development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":403438,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":773055,"name":"Kyle Leix","orcid":null,"position":1,"is_corresponding":false},{"id":672172,"name":"Emily J. Sherman","orcid":"0000-0002-3632-271X","position":2,"is_corresponding":false},{"id":93854,"name":"Carmen Mirabelli","orcid":"0000-0002-4785-5482","position":3,"is_corresponding":false},{"id":657940,"name":"Andrew A. Kennedy","orcid":null,"position":4,"is_corresponding":false},{"id":226886,"name":"Adam S. Lauring","orcid":"0000-0003-2906-8335","position":5,"is_corresponding":false},{"id":657374,"name":"Andrew W. Tai","orcid":"0000-0002-6877-450X","position":6,"is_corresponding":false},{"id":288650,"name":"Christiane E. Wobus","orcid":"0000-0001-5286-0924","position":7,"is_corresponding":false},{"id":499038,"name":"Brian T. Emmer","orcid":"0000-0001-7365-1021","position":8,"is_corresponding":false},{"id":784640,"name":"Juliana Bragazzi Cunha","orcid":"0000-0002-3493-2960","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:20:36.280647Z","pmid":"36909579","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}