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.
摘要：
肥胖已被确定为2019年冠状病毒病(COVID-19)和其他传染病患者严重结局的独立危险因素。这里,我们使用鼠β-冠状病毒建立了COVID-19的小鼠模型，小鼠肝炎病毒1（MHV-1）。暴露于MHV-1的C57BL/6和C3H/HeJ小鼠出现轻度和重度疾病，分别。肥胖C57BL/6小鼠出现与瘦对照相似的临床表现。相比之下,所有肥胖的C3H/HeJ小鼠在感染后8天死亡，相比之下，瘦肉对照组的死亡率为50%。值得注意的是,暴露于MHV-1的瘦和肥胖C3H/HeJ小鼠均出现与严重人类COVID-19一致的肺部病变，并有明显的弥漫性肺泡损伤（DAD）证据。为了确定肥胖C3H/HeJ小鼠疾病结局恶化的早期预测生物标志物，我们对感染后2天的全血RNA进行了测序,并评估了基因和通路表达的变化.肥胖C3H/HeJ小鼠感染后的许多途径发生了独特的改变，与患有严重COVID-19的人类中发现的途径一致。此外，我们观察到感染的肥胖小鼠与瘦小鼠相比，与未折叠的蛋白质反应和脂质代谢相关的基因表达发生了变化，提示在疾病结果的严重程度中的作用。这项研究为研究COVID-19提供了一种新的模型，并阐明了肥胖和其他宿主严重疾病结局的潜在机制。
