{"doi":"10.3389/fcimb.2025.1513687","title":"Diabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling","abstract":"Comorbidities, including obesity and type 2 diabetes mellitus (T2DM), are associated with increased disease severity and mortality following SARS-CoV-2 infection. Here, we investigated virus-host interactions under the effects of these comorbidities in diet-induced obesity (DIO) and leptin receptor-deficient (T2DM) mice following infection with SARS-CoV-2. DIO mice, as well as their lean counterparts, showed limited susceptibility to SARS-CoV-2 infection. In contrast, T2DM mice showed exacerbated pulmonary SARS-CoV-2 replication and delayed viral clearance associated with down-regulation of innate and adaptative immune gene signatures, ineffective type I interferon response, and delayed SARS-CoV-2-specific cell-mediated immune responses. While T2DM mice showed higher and prolonged SARS-CoV-2-specific immunoglobulin isotype responses compared to their lean counterparts, neutralizing antibody levels were equivalent. By silencing the leptin receptor in vitro using a human alveolar epithelial cell line, we observed an increase in SARS-CoV-2 replication and type I interferons. Altogether, our data provides for the first time evidence that disruption of leptin receptor signaling leading to obesity and T2DM induces altered type I interferon and cell-mediated responses against SARS-CoV-2, mediating increased viral replication and delayed clearance. These data shed light on the alteration of the innate immune pathway in the lung using in-depth transcriptomic analysis and on adaptive immune responses to SARS-CoV-2 under T2DM conditions. Finally, this study provides further insight into this risk factor aggravating SARS-CoV-2 infection and understanding the underlying cellular mechanisms that could help identify potential intervention points for this at-risk population.","journal":"Frontiers in Cellular and Infection Microbiology","year":2025,"id":540554,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":468035,"name":"Udeni B. R. Balasuriya","orcid":"0000-0003-0609-678X","position":1,"is_corresponding":false},{"id":849608,"name":"Anna E. Tseng","orcid":"0000-0003-4791-374X","position":2,"is_corresponding":false},{"id":559047,"name":"Nicholas A. Crossland","orcid":"0000-0003-3873-9188","position":3,"is_corresponding":false},{"id":427841,"name":"Jacqueline M. Stephens","orcid":"0000-0002-3796-9531","position":4,"is_corresponding":false},{"id":1059810,"name":"Wellesley Dittmar","orcid":null,"position":5,"is_corresponding":false},{"id":1282935,"name":"Jarosław Staszkiewicz","orcid":null,"position":6,"is_corresponding":false},{"id":218443,"name":"Jüergen A. Richt","orcid":"0000-0001-7308-5672","position":7,"is_corresponding":false},{"id":468033,"name":"Mariano Carossino","orcid":"0000-0003-3864-5915","position":8,"is_corresponding":false},{"id":953142,"name":"Côme Thieulent","orcid":"0000-0001-7402-5989","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"40125513","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":[]}