Proposed in response to a ?Dear colleague letter? to fund research to fight the coronavirus pandemic, this project will study the impact of obesity, diabetes, and gender on disease severity and transmission in a mouse model of coronavirus disease. Mouse models must be used to study this disease since humans cannot be infected due to ethical reasons. Obese and diabetic people, along with males, are at a higher risk for severe coronavirus disease, which is concerning since 42% of Americans are obese, 30% are pre-diabetic, and 9.4% have diabetes, while 49.2% are male. It is currently unknown why these groups of people are at higher risk for severe disease, a question that must be answered to develop effective treatments and public health campaigns. The value of this research to the taxpayers is that the information gained will generate data necessary to create effective vaccines and antivirals and identify ways to control coronavirus transmission. In addition, this model will have broad interest to researchers studying the modeling of transmission dynamics, virus-host interactions, immunology, antivirals, and understanding basic virus biology. If successful, these studies will provide a model with the potential to transform the way research with these SARS-CoV-2 is currently done. The borader impacts of this work include mentoring a graduate student and undergraduate students in infectious disease research to train the next generation of STEM researchers.

Currently, no models to study the impacts of co-morbidities or identify biomarkers of disease severity or transmission on COVID-19 exist. The goals of this project are to define the impact of obesity, diabetes, and sex on disease severity and transmission in the context of different viral and host genotypes using a natural model of mouse infection with the murine hepatitis virus (MHV). The two strains of mice display differential susceptibility to severe disease to the two strains of mouse coronavirus?from asymptomatic to 80% mortality. Furthermore, MHV is highly transmissible mouse-to-mouse, which is unlikely to occur with SARS-CoV-2 infection in mice. Accordingly, this is an excellent model system with which to gather immunological, viral, and other data from infected mice to identify potential biomarkers of severe disease or transmission. Levels of MHV in the blood and oral passages, gene expression, cytokine levels, blood parameters, clinical disease, tissue pathology, and mortality will be the phenotypes used to compare to disease severity and transmission to identify associations. The hypothesis is that pro-inflammatory cytokines (notably interleukin-6, tumor necrosis factor-alpha, and CXCL10) and concentration of virus in the blood or oral passages can be used to predict disease severity and transmission, respectively. These studies will increase understanding of the underlying biology of coronaviruses, virus and host interactions, the genotype, phenotype, and environmental factors influencing coronavirus disease and transmission, and may identify biomarkers to predict disease severity and transmission in people with COVID-19. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Joanna Shisler
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