COVID 19 Respiratory and CNS Pathogenesis in Geriatric Rhesus Monkeys

Project Summary: Although coronaviruses primarily cause respiratory and intestinal infections, they also have the potential to cause central nervous system (CNS) complications. There is accumulating evidence of neurological damage in COVID-19 patients, with neurological symptoms correlating with disease severity. The primary receptor for SARS-CoV-2, the angiotensin converting enzyme- 2 (ACE-2), is expressed by neurons and other cells in the brain providing a strong rationale to investigate the impact of SARS-CoV-2 infection on the CNS. The goals of this proposal are to understand CNS viral dissemination and neuroinflammation following SARS-CoV-2 infection in geriatric rhesus macaques. Because preventing viral entry into the CNS maybe a lifesaving measure in COVID-19 patients, this work is highly urgent. Additionally, susceptibility of geriatric patients to COVID-19 associated respiratory and CNS complications suggests a role for age-associated immunosenescence and neurodegeneration in COVID-19 morbidity. Addressing these questions in the framework of human studies is challenging; therefore, studies in the COVID-19 rhesus model are critically needed. The goal of this work is to urgently address CNS complications as it relates to age using a COVID-19 rhesus model. Our Aims are: Aim 1: Characterize SARS-CoV-2 dissemination to CNS and neuroinflammation in young and geriatric rhesus monkeys. Aim 2: Determine Efficacy of Convalescent Plasma Therapy in preventing COVID-19 respiratory and CNS complications in geriatric monkeys. Urgency and relevance to NOT-AG-20-022: This proposal aligns with the research interests of Division of Aging Biology and Division of Neuroscience. Our rhesus studies are focused on understanding disease pathogenesis in older animals and are highly relevant to scope and purpose of this NOSI. Work in animal models is vital to fully comprehend how SARS-CoV-2 gains access to the CNS and define crucial interventions to resolve infection without long-term neurocognitive damage. Feasibility: This urgent competitive revision is within the expertise of the PIs of the original grant and we have the resources, reagents, and collaborators at the CNPRC to achieve the proposed goals. We have included as Key Personnel, Dr. Chris Miller and Dr. Koen Von Rompay who are part of the CNPRC team developing COVID-19 rhesus model. Our strong collaborations with the UC Medical Center clinicians treating COVID-19 patientsgives us a significant advantage in understanding the disease process and identifying and testing interventions with direct translational relevance. Work in animal models is vital to fully understand how/why SARS-CoV-2 in more pathogenic in older adults, gains access to the CNS and to define crucial interventions to resolve infection without long-term pathology. All the lab work will be done in certified (by State, County, and UC systemregulators) BSL3 laboratories at the CIID and the AG BSL3 animal facilities at the CNPRC. The work has been approved by the UC Davis IBC and will be monitored by biosafety officers at UCD main campus,CIID, and CNPRC.