Diabetes Exacerbates SARS-CoV-2 Replication Through Ineffective Pulmonary Interferon Responses, Delayed Cell-mediated Immunity, and Disruption of Leptin Signaling

Come Thieulent ^1,2,3 Udeni Balasuriya ^1,2,3 Anna Tseng ⁴ Nicholas A Crossland ⁴ Jacqueline M Stephens ⁵ Wellesley Dittmar ^1,2,3 Jaroslaw Staszkiewicz ⁵ Juergen A Richt ⁶ Mariano Carossino ^1,2,3*

• ¹ Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, United States
• ² Louisiana Animal Disease Diagnostic Laboratory, School of Veterinary Medicine, Louisiana State University, Baton Rouge, United States
• ³ Louisiana State University, Baton Rouge, United States
• ⁴ Boston University, Boston, Massachusetts, United States
• ⁵ Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
• ⁶ Kansas State University, Manhattan, Kansas, United States

Comorbidities, including obesity and type 2 diabetes (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 a 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 indepth transcriptomics 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.