Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease COVID-19 Supplement

Project Summary: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and itsresulting disease (COVID-19) emerged as an unprecedented worldwide healthcare crisis. COVID-19 primarilymanifests as a lower respiratory tract infection and viral pneumonia; however, neurotropism is a commonfeature of coronaviruses (CoVs) and has been documented for almost all betacoronaviruses, the clade towhich SARS-CoV-2 belongs. It was reported that 36% of COVID-19 patients develop neurologic symptoms,but whether these are due to CNS infection, systemic inflammatory response, or intensive care unit delirium isunknown. Advanced age is a significant risk factor for developing severe infection from SARS-CoV-2. Aging isassociated with compromised cellular immunity and blood brain barrier dysfunction, which may increase thevulnerability of the CNS to infection and long-term damage from systemic infections. Neuroinflammation isrecognized as contributing to disorders of the central nervous system (CNS) including Alzheimer's disease(AD). Our overarching hypothesis is that viral encephalitis enhances inflammatory events that accelerate CNSaging processes and contribute to the development of AD pathology. The original application proposed to useWest Nile virus (WNV) as a model of viral encephalitis to examine behavioral, cellular, and molecularmechanisms of CNS recovery. Here we propose to enhance this research by investigating a murine CoVmodel, mouse hepatitis virus A-59. Like WNV, CoVs are enveloped positive-stranded RNA viruses, but havedistinct effects in the CNS. The addition of this CoV model will augment the original scope of the proposal byallowing the comparison of results from each of the two models to determine universal aging processes thatresult from viral infection. In this supplement, we propose to test the hypothesis that advanced age increasesthe risk of lethal neurotropic infection by CoV and that inflammatory processes initiated by infection maycontribute to the pathogenesis of AD. Aim 1 will determine the impact of advanced age on acute viral infectionand antiviral response. Aim 2 will identify the effect of advanced age on microglial response to infection. Aim 3will investigate the impact of viral encephalitis on pathological Tau accumulation. These studies will addressthe urgent need to understand how aging impacts CoV infections, the impact of viral encephalitis on agingprocesses in the CNS, and their contribution to neurodegenerative diseases. The experiments proposed herewill be analyzed in parallel with our established model of WNV to enhance the goals of the original proposal.