{"doi":"10.1101/2021.07.23.453505","title":"SARS-CoV-2 Exploits Sexually Dimorphic and Adaptive IFN and TNFa Signaling to Gain Entry into Alveolar Epithelium","abstract":"Abstract Infection of the alveolar epithelium constitutes a bottleneck in the progression of COVID-19 to SARS presumably due to the paucity of viral entry receptors in alveolar epithelial type 1 and 2 cells. We have found that the male alveolar epithelial cells express twice as many ACE2 and TMPRSS2 entry receptors as the female ones. Intriguingly, IFN and TNF-α signaling are preferentially active in male alveolar cells and induce binding of the cognate transcription factors to the promoters and lung-active enhancers of ACE2 and TMPRSS2 . Cotreatment with IFN-I and III dramatically increases expression of the receptors and viral entry in alveolar epithelial cells. TNFα and IFN-II, typically overproduced during the cytokine storm, similarly collaborate to induce these events. Whereas JAK inhibitors suppress viral entry induced by IFN-I/III, simultaneous inhibition of IKK/NF- κ B is necessary to block viral entry induced by TNFα and IFN-II. In addition to explaining the increased incidence of SARS in males, these findings indicate that SARS-Cov-2 hijacks epithelial immune signaling to promote infection of the alveolar epithelium and suggest that JAK inhibitors, singly and in combination with NF-KB inhibitors, may exhibit efficacy in preventing or treating COVID-19 SARS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221257,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"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":821263,"name":"Sreeharsha Gurrapu","orcid":"0000-0003-2195-2767","position":1,"is_corresponding":false},{"id":686910,"name":"Hong Chen","orcid":"0000-0003-3605-6551","position":2,"is_corresponding":false},{"id":821876,"name":"Sara Laudato","orcid":null,"position":3,"is_corresponding":false},{"id":821264,"name":"Emily G. Caggiano","orcid":"0000-0001-6729-120X","position":4,"is_corresponding":false},{"id":397264,"name":"Yan Jiang","orcid":"0000-0002-1945-4200","position":5,"is_corresponding":false},{"id":821877,"name":"Hsiang-Hsi Ling","orcid":null,"position":6,"is_corresponding":false},{"id":417629,"name":"Filippo G. Giancotti","orcid":"0000-0002-0541-9519","position":7,"is_corresponding":false},{"id":584274,"name":"Yan Wang","orcid":"0000-0001-8601-9121","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-18T23:53:55.215284Z","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":[]}