Diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected golden hamsters

Obese patients with nonalcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. There is an urgent need for new treatments that lower the severity of COVID-19 in this vulnerable population. To better replicate the human context, we set up a diet-induced model of obesity associated with dyslipidemia and NASH in the golden hamster (known to be a relevant preclinical model of COVID-19). A 20-week, free-choice diet induces obesity, dyslipidemia and NASH (liver inflammation and fibrosis) in golden hamsters. Obese NASH hamsters have higher blood and pulmonary levels of inflammatory cytokines. In the early stages of a SARS-CoV-2 infection, the lung viral load and inflammation levels were similar in lean hamsters and obese NASH hamsters. However, obese NASH hamsters showed worse recovery (i.e. less resolution of lung inflammation 10 days post-infection (dpi), and lower body weight recovery on dpi 25). Obese NASH hamsters also exhibited higher levels of pulmonary fibrosis on dpi 25. Unlike lean animals, obese NASH hamsters infected with SARS-CoV-2 presented long-lasting dyslipidemia and systemic inflammation. Relative to lean controls, obese NASH hamsters had lower serum levels of angiotensin-converting enzyme 2 activity and higher serum levels of angiotensin II - a component known to favor inflammation and fibrosis. Even though the SARS-CoV-2 infection resulted in early weight loss and incomplete body weight recovery, obese NASH hamsters showed sustained liver steatosis, inflammation, hepatocyte ballooning, and marked liver fibrosis on dpi 25.<strong> </strong>We conclude that diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected hamsters. This model might be of value in characterizing the pathophysiologic mechanisms of COVID-19 and in evaluating the efficacy of treatments for the severe forms of COVID-19 observed in obese patients with NASH.非酒精性脂肪性肝炎（nonalcoholic steatohepatitis，NASH）肥胖患者罹患重症新型冠状病毒肺炎（coronavirus disease 2019，COVID-19）的风险显著升高，针对这一脆弱人群，亟需开发可降低COVID-19病情严重程度的新型治疗方案。为更精准地复现人体病理情境，本研究以叙利亚金黄地鼠（golden hamster，被证实为COVID-19研究的相关临床前模型）为实验对象，构建了饮食诱导的肥胖合并血脂异常及NASH模型。通过20周自由选择饮食方案，可诱导金黄地鼠出现肥胖、血脂异常及NASH（肝脏炎症与纤维化）。肥胖NASH金黄地鼠的血液及肺部炎症细胞因子水平显著升高。在严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）感染早期，瘦型金黄地鼠与肥胖NASH金黄地鼠的肺部病毒载量及炎症水平无明显差异。然而，肥胖NASH金黄地鼠的病情恢复效果更差：感染后10天（dpi）肺部炎症缓解程度更低，感染后25天（dpi）的体重恢复情况也更差。至感染后25天，肥胖NASH金黄地鼠还表现出更为严重的肺部纤维化。与瘦型对照组动物不同，感染SARS-CoV-2的肥胖NASH金黄地鼠出现了持续的血脂异常与全身性炎症反应。与瘦型对照组相比，肥胖NASH金黄地鼠的血清血管紧张素转换酶2（angiotensin-converting enzyme 2，ACE2）活性更低，而血清血管紧张素Ⅱ（angiotensin II）水平更高——该物质已被证实可促进炎症与纤维化进程。尽管SARS-CoV-2感染会导致早期体重下降且体重恢复不完全，但至感染后25天，肥胖NASH金黄地鼠仍表现出持续的肝脏脂肪变性、炎症、肝细胞气球样变及显著的肝脏纤维化。综上，饮食诱导的肥胖及NASH会损害SARS-CoV-2感染金黄地鼠的病情恢复能力。该模型可用于阐明COVID-19的病理生理机制，并用于评估针对NASH肥胖患者重症COVID-19的治疗方案疗效。