biostudies-literatureUnknown15Thieulent CJComorbidities, 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-CoVFrontiers in cellular and infection microbiology1513687https://www.ebi.ac.uk/biostudies/studies/S-EPMC11925909biostudies-literatureDiabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling.PMC11925909Stephens JMRicht JACarossino MStaszkiewicz JThieulent CJTseng ADittmar WBalasuriya UBRCrossland NAfalseDiabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling.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-CoV2025-01-01T00:00:00Z20252026-06-02T17:27:07.388Z2025-04-05T22:08:35.996ZS-EPMC119259094012551310.3389/fcimb.2025.1513687