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

Katherine S Lee; Brynnan P Russ; Ting Y Wong; Alexander M Horspool; Michael T Winters; Mariette Barbier; Justin R Bevere; Ivan Martinez; F Heath Damron; Holly A Cyphert

doi:10.1016/j.isci.2022.105038

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

iScience. 2022 Oct 21;25(10):105038. doi: 10.1016/j.isci.2022.105038. Epub 2022 Sep 2.

Authors

Katherine S Lee^{1

2}, Brynnan P Russ^{1

2}, Ting Y Wong^{1

2}, Alexander M Horspool^{1

2}, Michael T Winters¹, Mariette Barbier^{1

2}, Justin R Bevere^{1

2}, Ivan Martinez^{1

3}, F Heath Damron^{1

2}, Holly A Cyphert⁴

Affiliations

¹ Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, USA.
² Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA.
³ West Virginia University Cancer Institute, School of Medicine, Morgantown, WV, USA.
⁴ Department of Biological Sciences, Marshall University, Huntington, WV, USA.

Abstract

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.

Keywords: Human metabolism; Virology.