Diabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling

Authors

• Côme J. Thieulent, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Udeni B R Balasuriya, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Anna Tseng, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
• Nicholas A. Crossland, Boston University Chobanian & Avedisian School of Medicine, Boston, MA
• Jacqueline M. Stephens, Pennington Biomedical Research Center, Baton Rouge, LA
• Wellesley Dittmar, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Jaroslaw Staszkiewicz, Pennington Biomedical Research Center, Baton Rouge, LA
• Juergen A. Richt, Kansas State University College of Veterinary Medicine, Manhattan, KS
• Mariano Carossino, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA

Document Type

Article

Publication Date

3-7-2025

Publication Title

Frontiers in Cellular and Infection Microbiology

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.

First Page

1

Last Page

24

DOI

10.3389/fcimb.2025.1513687

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Thieulent, Côme J.; Balasuriya, Udeni B R; Tseng, Anna; Crossland, Nicholas A.; Stephens, Jacqueline M.; Dittmar, Wellesley; Staszkiewicz, Jaroslaw; Richt, Juergen A.; and Carossino, Mariano, "Diabetes exacerbates SARS-CoV-2 replication through ineffective pulmonary interferon responses, delayed cell-mediated immunity, and disruption of leptin signaling" (2025). LSU-LCMC Cancer Center Faculty Publications. 192.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/192
10.3389/fcimb.2025.1513687