Humoral Immune Mechanisms of Acute and Chronic Neurologic Sequelae of COVID-19

PROJECT SUMMARY COVID-19 is associated with a growing number of peripheral and central nervous system complications. It has become clear that a subset of these syndromes, including acute necrotizing encephalopathy, steroid- responsive encephalitis and Guillain-Barré syndrome, are likely due to direct viral neuroinvasion and/or autoimmunity triggered by SARS-CoV-2. There is an urgent need to prospectively investigate the acute and chronic neurologic complications of COVID-19 and determine which syndromes are neuroinflammatory in origin. While anti-viral therapeutics are still being developed for SARS-CoV-2, autoimmune CNS conditions can be very responsive to immunosuppression. Thus, identifying biomarkers for a subset of COVID-19 patients with autoimmune CNS syndromes in particular could immediately impact clinical management. Over the past 8 years, a unique interdisciplinary team of neurologists and basic scientists at UCSF was formed to develop and deploy an integrated approach to rapidly identify microbial nucleic acid, anti-viral antibodies and anti-neural antibodies associated with encephalitis, with the explicit intent to discover and validate clinically actionable biomarkers in addition to uncovering the fundamental mechanisms of disease pathogenesis underlying these syndromes. The centerpiece of these efforts is an ongoing patient cohort called the NID (Neuroinflammatory Disease) cohort, consisting of patients with suspected infectious or inflammatory encephalitis. This cohort is now >1,400 patients referred by clinicians at UCSF and from other centers around the world. Already, this cohort has spurred the development of the first ever clinically validated cerebrospinal fluid metagenomic next-generation sequencing assay, the identification of a novel paraneoplastic autoimmune syndrome with important implications for men with seminoma and the identification of enteroviral CSF antibodies in children with acute flaccid myelitis. Here, we propose to adapt this existing clinical research and laboratory infrastructure to enroll and investigate the urgent question whether COVID-19 patients with ongoing neurologic sequelae have CNS inflammation. We will perform this work in collaboration with colleagues at the NIH, Yale University as well as at UCSF Medical Center, Zuckerberg San Francisco General Hospital and UCSF Benioff Children's Hospital. Using our unique clinical and molecular approach, we will investigate this hypothesis through the following specific aims: Aim 1: Characterize autoantibodies in the CSF of COVID-19 patients with acute and chronic neurologic syndromes Aim 2: Identify CSF specific antibody repertoires in COVID-19 patients with neurologic complications using high-resolution SARS-CoV-2 proteome-wide antibody profiling Aim 3: Elucidate autoantibody pathogenicity through production of monoclonal antibodies from clonally expanded CSF B cells in COVID-19 patients to enable the development of animal models of disease