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-Barr syndrome, are likely due autoimmunity triggered by SARS-CoV-2 infection. 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 ? particularly those caused by para- infectious autoimmunity. 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 could immediately impact clinical management. Over the past 7 years, a unique interdisciplinary team of neurologists and basic scientists at UCSF was formed to develop and deploy an integrated approach to rapidly 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 >1,500 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. We seek emergency funding to accelerate our work on identifying anti- neural autoantibodies associated with SARS-CoV-2 infection in patients with neurologic syndromes in 1 immediate aim.
Aim 1 : Identify autoantibodies in the CSF of COVID-19 patients with neurologic syndromes.
Patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are increasingly recognized to be suffering from a wide variety of peripheral and central nervous system complications. While a large proportion of the neurologic sequelae are due to complications of systemic disease (e.g., hypoxia- ischemia, hypercoagulability, renal failure, etc), it is also becoming apparent that some patients have central nervous system inflammation as a result of a para-infectious immune processes that may be autoantibody- mediated. This project leverages an innovative and high-throughput pipeline for identifying human proteome- wide detection of autoantibodies from sera and cerebrospinal fluid collected from COVID-19 patients to better understand neuropathogenesis and provide insights into neural mechanisms that underly complex brain functions ranging from coordination to maintenance of mood and personality.
