The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resulting disease (COVID-19) emerged as an unprecedented worldwide healthcare crisis. COVID-19 primarily manifests as a lower respiratory tract infection and viral pneumonia; however, neurotropism is a common feature of coronaviruses (CoVs) and has been documented for almost all betacoronaviruses, the clade to which 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 is unknown. Advanced age is a significant risk factor for developing severe infection from SARS-CoV-2. Aging is associated with compromised cellular immunity and blood brain barrier dysfunction, which may increase the vulnerability of the CNS to infection and long-term damage from systemic infections. Neuroinflammation is recognized 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 CNS aging processes and contribute to the development of AD pathology. The original application proposed to use West Nile virus (WNV) as a model of viral encephalitis to examine behavioral, cellular, and molecular mechanisms of CNS recovery. Here we propose to enhance this research by investigating a murine CoV model, mouse hepatitis virus A-59. Like WNV, CoVs are enveloped positive-stranded RNA viruses, but have distinct effects in the CNS. The addition of this CoV model will augment the original scope of the proposal by allowing the comparison of results from each of the two models to determine universal aging processes that result from viral infection. In this supplement, we propose to test the hypothesis that advanced age increases the risk of lethal neurotropic infection by CoV and that inflammatory processes initiated by infection may contribute to the pathogenesis of AD.
Aim 1 will determine the impact of advanced age on acute viral infection and antiviral response.
Aim 2 will identify the effect of advanced age on microglial response to infection.
Aim 3 will investigate the impact of viral encephalitis on pathological Tau accumulation. These studies will address the urgent need to understand how aging impacts CoV infections, the impact of viral encephalitis on aging processes in the CNS, and their contribution to neurodegenerative diseases. The experiments proposed here will be analyzed in parallel with our established model of WNV to enhance the goals of the original proposal.
The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resulting disease (COVID-19) emerged as an unprecedented worldwide healthcare crisis that disproportionately affects aged people. COVID-19 primarily manifests as a lower respiratory tract infection and viral pneumonia; however, neurotropism is a common feature of coronaviruses. In this supplement, we propose to assess whether advanced age increases the risk of neurotropic infection by coronaviruses and whether inflammatory processes initiated by infection may contribute to pathology associated with Alzheimer?s disease.