Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities

Abstract

Obesity has been identified as an independent risk factor for severe outcomes in humans with coronavirus disease 2019 (COVID‐19) and other infectious diseases. Here, we established a mouse model of COVID‐19 using the murine betacoronavirus, mouse hepatitis virus 1 (MHV‐1). C57BL/6 and C3H/HeJ mice exposed to MHV‐1 developed mild and severe disease, respectively. Obese C57BL/6 mice developed clinical manifestations similar to those of lean controls. In contrast, all obese C3H/HeJ mice succumbed by 8 days postinfection, compared to a 50% mortality rate in lean controls. Notably, both lean and obese C3H/HeJ mice exposed to MHV‐1 developed lung lesions consistent with severe human COVID‐19, with marked evidence of diffuse alveolar damage (DAD). To identify early predictive biomarkers of worsened disease outcomes in obese C3H/HeJ mice, we sequenced RNA from whole blood 2 days postinfection and assessed changes in gene and pathway expression. Many pathways uniquely altered in obese C3H/HeJ mice postinfection aligned with those found in humans with severe COVID‐19. Furthermore, we observed altered gene expression related to the unfolded protein response and lipid metabolism in infected obese mice compared to their lean counterparts, suggesting a role in the severity of disease outcomes. This study presents a novel model for studying COVID‐19 and elucidating the mechanisms underlying severe disease outcomes in obese and other hosts.