Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a global epidemiological concern as it continues to give rise to new variants exhibiting increased transmissibility and disease-causing potential1,2. As of 14th January, 2024, SARS-CoV-2 was responsible for ~774 million confirmed cases and ~7 million deaths globally and ~103 million confirmed cases and 1.2 million deaths in the U.S. alone3. The clinical manifestations range from mild respiratory symptoms to pneumonia, and in most severe instances, multi-organ failure and death4. Several epidemiological studies have shown strong associations between disease severity and co-morbidities, such as hypertension, diabetes, old age, cardiovascular diseases, and obesity5-11. More severe cases and deaths related to COVID-19 have been associated with macrophage activation12, caused by a dysregulated host immune response13.
Obesity has been identified as an independent risk factor for severe COVID-1914-18 and has been associated with chronic systemic inflammation19,20. However, most of these inferences are correlative and are based either on data from epidemiological studies7,8,11,15,17 or from studies performed in non-natural hosts of SARS-CoV-221,22. Therefore, a relevant model of coronavirus infection, which mimics SARS-CoV-2 infection in humans, is needed to study the impact of obesity on coronavirus disease outcome. We hypothesized that this model would be useful for identifying biomarkers associated with disease severity in COVID-19 patients, which could have prognostic value for risk stratification of patients with COVID-19.
To this end, we used C57BL/6N and C3H/HeJ mouse models of diet-induced obesity and inoculated them with mouse hepatitis virus 1 (MHV-1), a pneumotropic betacoronavirus which has been previously used to study SARS-CoV-1 infection23-25. We observed more severe disease in obese C3H/HeJ mice exposed to MHV-1 including increased weight loss, mortality, and tissue pathology. Moreover, RNA sequencing (RNAseq) analysis of whole blood RNA showed commonly altered genes and pathways between MHV-1 infected obese C3H/HeJ mice and humans with severe COVID-19 suggesting the relevance of our mouse model in identifying biomarkers of severe COVID-19 disease outcomes.