Obesity and metabolic dysfunction drive sex-associated differential disease profiles in hACE2-mice challenged with SARS-CoV-2

• Published in: iScience Vol. 25; no. 10; p. 105038
• Main Authors: Lee, Katherine S., Russ, Brynnan P., Wong, Ting Y., Horspool, Alexander M., Winters, Michael T., Barbier, Mariette, Bevere, Justin R., Martinez, Ivan, Damron, F. Heath, Cyphert, Holly A.
• Format: Journal Article Web Resource
• Language: English
• Published: Amsterdam Elsevier Inc 21.10.2022; Elsevier BV; Elsevier
• Subjects: Human metabolism; Virology; Human metabolism; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105038

Severe outcomes from SARS-CoV-2 infection are highly associated with preexisting comorbid conditions like hypertension, diabetes, and obesity. We utilized the diet-induced obesity (DIO) model of metabolic dysfunction in K18-hACE2 transgenic mice to model obesity as a COVID-19 comorbidity. Female DIO, but not male DIO mice challenged with SARS-CoV-2 were observed to have shortened time to morbidity compared to controls. Increased susceptibility to SARS-CoV-2 in female DIO was associated with increased viral RNA burden and interferon production compared to males. Transcriptomic analysis of the lungs from all mouse cohorts revealed sex- and DIO-associated differential gene expression profiles. Male DIO mice after challenge had decreased expression of antibody-related genes compared to controls, suggesting antibody producing cell localization in the lung. Collectively, this study establishes a preclinical comorbidity model of COVID-19 in mice where we observed sex- and diet-specific responses that begin explaining the effects of obesity and metabolic disease on COVID-19 pathology. [Display omitted] •Transcriptomic analysis of infected lungs revealed unique sex-dependent differences•Obese female mice have high viral RNA burden and interferon production in the lung•Male mice have altered antibody and T cell response gene profiles after viral challenge•Metabolic dysfunction comorbidity can be studied in the hACE2 mouse model of COVID-19 Virology; Human metabolism