{"doi":"10.3389/fimmu.2023.1284148","title":"IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide","abstract":"Introduction The COVID-19 pandemic has highlighted the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such mediator is interferon-g (IFN-γ), which, when administered to infected patients, is reported to result in viral clearance and resolution of pulmonary symptoms. IFN-γ treatment of a human lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the mechanism for this antiviral response was not identified. Methods Given that IFN-γ has been shown to trigger antiviral activity via the generation of nitric oxide (NO), we investigated whether IFN-γ induction of antiviral activity against SARS-CoV-2 infection is dependent upon the generation of NO in human pulmonary epithelial cells. We treated the simian epithelial cell line Vero E6 and human pulmonary epithelial cell lines, including A549-ACE2, and Calu-3, with IFN-γ and observed the resulting induction of NO and its effects on SARS-CoV-2 replication. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) was employed to assess the dependency on NO production. Additionally, the study examined the effect of interleukin-1b (IL-1β) on the IFN-g-induced NO production and its antiviral efficacy. Results Treatment of Vero E6 cells with IFN-γ resulted in a dose-responsive induction of NO and an inhibitory effect on SARS-CoV-2 replication. This antiviral activity was blocked by pharmacologic inhibition of iNOS. IFN-γ also triggered a NO-mediated antiviral activity in SARS-CoV-2 infected human lung epithelial cell lines A549-ACE2 and Calu-3. IL-1β enhanced IFN-γ induction of NO, but it had little effect on antiviral activity. Discussion Given that IFN-g has been shown to be produced by CD8+ T cells in the early response to SARS-CoV-2, our findings in human lung epithelial cell lines, of an IFN-γ-triggered, NO-dependent, links the adaptive immune response to an innate antiviral pathway in host defense against SARS-CoV-2. These results underscore the importance of IFN-γ and NO in the antiviral response and provide insights into potential therapeutic strategies for COVID-19.","journal":"Frontiers in Immunology","year":2023,"id":348891,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"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":56238,"name":"Paul Krogstad","orcid":"0000-0001-6191-6213","position":1,"is_corresponding":false},{"id":328879,"name":"Rosane M. B. Teles","orcid":"0000-0003-2908-3244","position":2,"is_corresponding":false},{"id":236681,"name":"Priscila R. Andrade","orcid":"0000-0001-5329-790X","position":3,"is_corresponding":false},{"id":795496,"name":"Jacob Rajfer","orcid":null,"position":4,"is_corresponding":false},{"id":477038,"name":"Mónica G. Ferrini","orcid":"0000-0001-5031-4188","position":5,"is_corresponding":false},{"id":377122,"name":"Otto O. Yang","orcid":"0000-0003-1970-8992","position":6,"is_corresponding":false},{"id":559602,"name":"Barry R. Bloom","orcid":"0000-0002-2068-7263","position":7,"is_corresponding":false},{"id":236685,"name":"Robert L. Modlin","orcid":"0000-0003-4720-031X","position":8,"is_corresponding":false},{"id":236683,"name":"Bruno Jorge de Andrade Silva","orcid":"0000-0002-0362-1860","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:10.335697Z","pmid":null,"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":[]}