tetano
Editor, Senior Moderator
Front Cell Infect Microbiol
. 2025 Mar 7:15:1513687.
doi: 10.3389/fcimb.2025.1513687. eCollection 2025. Diabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling
Côme J Thieulent[SUP] 1 2 [/SUP], Udeni B R Balasuriya[SUP] 1 2 [/SUP], Anna Tseng[SUP] 3 [/SUP], Nicholas A Crossland[SUP] 3 4 5 [/SUP], Jacqueline M Stephens[SUP] 6 [/SUP], Wellesley Dittmar[SUP] 1 2 [/SUP], Jaroslaw Staszkiewicz[SUP] 6 [/SUP], Juergen A Richt[SUP] 7 [/SUP], Mariano Carossino[SUP] 1 2 [/SUP]
Affiliations
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.
Keywords: COVID-19; SARS-CoV-2; T2DM; mouse model; obesity; respiratory infection; type 2 diabetes mellitus.
. 2025 Mar 7:15:1513687.
doi: 10.3389/fcimb.2025.1513687. eCollection 2025. Diabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling
Côme J Thieulent[SUP] 1 2 [/SUP], Udeni B R Balasuriya[SUP] 1 2 [/SUP], Anna Tseng[SUP] 3 [/SUP], Nicholas A Crossland[SUP] 3 4 5 [/SUP], Jacqueline M Stephens[SUP] 6 [/SUP], Wellesley Dittmar[SUP] 1 2 [/SUP], Jaroslaw Staszkiewicz[SUP] 6 [/SUP], Juergen A Richt[SUP] 7 [/SUP], Mariano Carossino[SUP] 1 2 [/SUP]
Affiliations
- PMID: 40125513
- PMCID: PMC11925909
- DOI: 10.3389/fcimb.2025.1513687
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.
Keywords: COVID-19; SARS-CoV-2; T2DM; mouse model; obesity; respiratory infection; type 2 diabetes mellitus.