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.