Coronaviruses, systems biology, aging, immunology, genetics, SARS-CoV, MERS-CoV, viral emergence

Utilizing severe coronavirus infections, the Menachery Lab seeks to define virus-host interactions that dictate disease outcomes taking advantage of three cutting edge platforms: 1) reverse genetic systems for virus generation, 2) a refined systems biology approach, and 3) diverse model systems for infection. Described below, the current projects provide insight into our approach and explore areas with implications for understanding infection and disease.

• Examine the dynamics of host-virus interactions within and between diverse viral families. Employing uniform experimental platforms, these systems based studies seek to identify common host pathways induced and/or antagonized by various pathogenic viruses. The approach also leverages differences between wild-type and mutant viruses to identify key processes that drive pathogenic outcomes. The overall goal is to derive mechanistic insight and develop novel avenues for antiviral treatment.
• Explore the pathogenic and emergence potential of novel CoVs. The outbreaks of both SARS and MERS-CoV underscore the need for continued surveillance of zoonotic viruses. While CoV sequences have been identified, minimal translational work has been undertaken. These studies evaluate the likelihood of emergence, pathogenic potential, and efficacy of current therapeutic platforms against existing coronavirus strains.
• Define age dependent changes to host immunity via viral infection. Infectious disease in the context of aging represents an opportunity to explore changes to immunity as well as gain insights into a leading cause of death among the elderly. Importantly, both SARS and MERS-CoV induce more severe infection and increased mortality in aged human patients. This phenotype is recapitulated in young and aged mouse models, allowing exploration of host virus interaction that change as a product of aging. These studies seek to identify, confirm, and validate changes in pathway activation as well as develop treatments to mitigate disease in the aged hosts.
• Examine the role of host diversity in susceptibility to infection. In addition to aging, host genetic diversity plays a critical role in the response to respiratory virus infection. Employing the Collaborative Cross (CC), a panel of recombinant inbred mice that captures genetic diversity similar to the human population, we observe a wide spectrum of phenotypes. These readouts can be dysregulated from each other, allowing fine mapping to define specific genetic components that drive phenotypic responses.