Diet-induced obesity and nash aggravate sars-cov-2 infection in golden syrian hamsters

Background: Patients with obesity and nonalcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. Novel drugs are urgently needed and may be evaluated in the golden Syrian hamster, a relevant preclinical model for SARS-CoV-2 infection. To better replicate the human context, we recently set-up a nutritional hamster model that develops obesity and metabolic comorbidities including dyslipidemia, NASH, and heart failure with preserved ejection fraction. We compared the deleterious effects of SARS-CoV-2 infection in lean versus obese hamsters. Methods: Male, 4-week-old golden Syrian hamsters were fed with a normal chow or high fat/cholesterol/fructose diet for 20 weeks. Lean or diet-induced obese/NASH hamsters were then intranasally infected with SARS-CoV-2. Hamsters were sacrificed at 4-, 7-, 10-, and 25-days post-infection for serum and organs collection. Lung viral load was assessed by plaque assay (Vero-E6 cells for TCID50 assay). Lung samples were also processed for gene expression by RT-qPCR. Histopathological scoring (H&E staining) and fibrosis assessment (Sirius Red staining) were performed on lungs and liver. Serum samples were used for lipids levels and analysis of the Renin Angiotensin System (RAS) components by mass spectrometry (LC-MS/MS). Results: Although body weight loss was similar during the first days after infection, obese hamsters did not recover their initial body weight at day 25, while lean individuals did. During the 25-day post-infection period, obese hamsters remained dyslipidemic and kept a significantly higher liver steatosis, inflammation, ballooning and fibrosis scores, as compared to lean hamsters. Lung viral load and expression of inflammatory genes were not statistically different between lean and obese hamsters. However, obese hamsters had significantly greater lung histopathological scoring at 10 days post-infection (p<0.05 vs. lean). Additionally, lung fibrosis was significantly higher in obese hamsters at 25 days post-infection (p<0.01 vs. lean). Obese hamsters also had significantly higher serum Angiotensin II levels at day 4 and day 7, a RAS component known to favor lung inflammation, fibrosis, and oedema. Conclusion: Diet-induced obesity and NASH aggravated SARS-CoV-2 infection in golden Syrian hamsters. This model will be useful to evaluate novel drugs targeting the severe forms of COVID-19 seen in patients with obesity and NASH.