Three coronaviruses (SARS-CoV1, MERS-CoV, and SARS-CoV2) have emerged from animals causing severe respiratory disease in humans. Little is known about the virus-host interactions which control disease severity and transmission, leaving society unprepared for the COVID-19 pandemic. An animal model that closely mimics SARS-CoV-2 infection and pathogenesis is needed to better inform and educate about the science of virus transmission and prevention. Mice are infected with their own, mouse-specific coronavirus [mouse hepatitis virus (MHV)] that causes respiratory disease and affects other organs, such as the heart, liver and spleen, like COVID-19. This proposal will utilize a MHV model of COVID-19 to understand disease progression and the factors involved using controlled conditions. The mouse model takes advantage of available mouse genetic tools, immunologic reagents, and detailed pathologic assessments to identify host factors, such as the type of immune cell infiltrates and cytokines produced that are associated with different disease severities. This analysis will provide insight into protective and deleterious host responses, which can identify processes to target for therapeutics. The development of this model system has the potential to be an efficient and cost effective tool to identify and screen treatment and prevention strategies that warrant escalation to more specific COVID-19 models, thereby making the best use of the limited infrastructure resources associated with the ABSL-3 requirements of actual SARS-CoV2 use. This is a Broader Impact because it will benefit society in the quest for COVID-19 therapeutics and vaccines.
Models of all levels of SARS-CoV2 disease in genetically diverse populations are urgently needed. It is hypothesized that the host and virus factors controlling the severity of coronavirus respiratory infections can be identified using natural murine coronavirus infections in diverse, yet genetically defined cohorts of mice. MHV are natural pathogens of mice that are well adapted to their host and vary in both their tropisms and their disease phenotype. The range of pathological lesions and host responses caused by MHV-1 and MHV-A59, with different virulence in the respiratory tract, will be characterized. The eight genetically diverse Collaborative Cross founder mouse strains will be used to represent the genetic diversity seen in large human populations. These studies will focus on lung pathology, but the heart, liver, kidney and spleen will also be evaluated. Mice will be inoculated with MHV-1 or MHV-A59. Tissues will be examined for pathologic changes. Fibrosis and immune cell infiltrates will be characterized using histochemical stains and immunohistochemistry. Viral titers, serum chemistry, coagulation, neutralizing antibodies and cytokines will be measured. Correlations between MHV strain, mouse strain, viral load, clinical disease, pathological lesions, and immune reactions will be determined. These studies are the first step to increase knowledge about the biology of SARS-CoV-2 infections. This RAPID award is made by the Symbiosis, Defense, and Self-recognition Program in the BIO Division of Integrative Organismal Systems, and, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act. It was co-reviewed by the BIO Division of Molecular and Cellular Biology Genetic Mechanisms cluster.
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.
