PROJECT SUMMARY/ABSTRACT: Rationale: The COVID-19 pandemic has affected over 42 million individuals in the United States and long-term complications are frequently reported, referred to as post-acute sequelae of SARS-CoV-2 (PASC). Even among survivors with mild acute illness, neurologic symptoms such as chronic fatigue, dysautonomia, and cognitive impairment are frequently reported. To date, the etiology and pathophysiology of neurologic PASC remain unclear; however, underlying autoantibodies and immune activation are suspected. In our prospective COVID-19 ID Persistence Cohort (C-PIC), more than half of COVID-19 survivors are reporting neurologic PASC at one year. We have identified an association between neurologic PASC with both SARS-CoV-2 specific antibodies and ANA. Specifically, nucleocapsid (NP) antibody levels are elevated compared to spike trimer (ST) antibody levels in participants with neurologic PASC. Furthermore, our preliminary data has identified a potential signal linking neurologic PASC and decreased gastrointestinal microbiota diversity. In this mentored career project, we hypothesize that autoimmunity, immune activation, and microbiome dysbiosis are associated with neurologic PASC. Candidate: As an Infectious Diseases physician with a master’s in public health and applied epidemiology and outbreak training through the Center for Disease Control and Prevention’s Epidemic Intelligence Service, I am uniquely positioned to study the epidemiology and determinants for neurologic PASC. My experience studying post- Ebola syndrome in Liberia provided me with the foresight to contribute viral persistence and sequelae aims to the C-PIC study, which includes longitudinal PASC survey data and biorepository specimens. Through the guidance of my outstanding multidisciplinary team of mentors, I plan to fulfill my training objectives of (1) developing expertise in advanced biostatistical analysis of survey data and (2) bridging translational research and descriptive cohort data. Environment: My team of mentors at Columbia University Irving Medical Center (CUIMC) are experts in epidemiology, biostatistics, immunology, and microbiome analysis. CUIMC also has a long track record of enabling young physician-scientists to develop independent and successful careers in academic medicine. Approach: We hypothesize that chronic fatigue, dysautonomia, and cognitive impairment sub-phenotypes of neurologic PASC have different underlying pathophysiology, including autoimmunity, immune activation, and microbiome dysbiosis. In Aim 1, we will characterize neurologic PASC epidemiology, trajectory, and sub-phenotypes using longitudinal neurologic PASC surveys. In Aim 2, we will identify associations between neurologic PASC with SARS-CoV-2 specific antibodies and autoantibodies. In Aim 3, we will identify associations between neurologic PASC and immune activation and explore the role of gut microbiota. This proposal provides an innovative approach to studying determinants for neurologic PASC, and the proposed training will facilitate my transition into an independently funded clinician-scientist.

PROJECT NARRATIVE Neurologic post-acute sequelae of SARS-CoV-2 (PASC) is an emerging threat. The trajectory and pathophysiology of PASC are poorly understood; however, underlying autoimmunity and persistent immune activation are suspected. This proposal aims to better characterize the sub-phenotypes and clinical course of neurologic PASC and to test for the role autoantibodies, persistent immune activation, and gut microbiota in a longitudinal cohort of COVID-19 survivors.