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Principal Investigator: SAMUEL JEREMY PLEASURE
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2022
Award: $623,479
Funding agency: National Institute of Neurological Disorders and Stroke
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
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><21+ years old><AIDP><Acute><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Adult><Adult Human><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Animal Disease Models><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Repertoire><Antigens><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Autoantibodies><Autoantigens><Autoimmune><Autoimmune Status><Autoimmune encephalitis><Autoimmune encephalopathy><Autoimmunity><Autologous Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Behavioral Assay><Bioassay><Biologic Assays><Biological Assay><Biological Markers><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Body Tissues><Brain><Brain Inflammation><Brain Nervous System><CNS Nervous System><COVID complications><COVID infected patient><COVID patient><COVID positive patient><COVID related complications><COVID-19><COVID-19 S protein><COVID-19 antibody><COVID-19 complications><COVID-19 infected patient><COVID-19 infection><COVID-19 neural sequela><COVID-19 patient><COVID-19 positive patient><COVID-19 related complications><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Cell Body><Cells><Central Nervous System><Cerebrospinal Fluid><Child><Child Youth><Children (0-21)><Children's Hospital><Chronic><Clinical><Clinical Management><Clinical Research><Clinical Study><Clinical Treatment Moab><CoV emergence><CoV-2><CoV2><Collaborations><Complex><Data><Detection><Development><Disease><Disorder><Disseminated Sclerosis><Dysfunction><Encephalitis><Encephalon><Encephalopathies><Enrollment><Epitope Mapping><Functional Metagenomics><Functional disorder><General Hospitals><Generations><Goals><Guillain Barré Syndrome><Guillaine-Barre Syndrome><HCoV><Human><Humoral Immunities><Immune><Immune Precipitation><Immune mediated therapy><Immune response><Immunes><Immunofluorescence><Immunofluorescence Immunologic><Immunological response><Immunologically Directed Therapy><Immunoprecipitation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Infection><Inflammation><Inflammatory><Infrastructure><Infusion><Infusion procedures><Lab Findings><Laboratories><Laboratory Finding><Landry's paralysis><Landry-Guillain-Barre Syndrome><Maintenance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Medical center><Metagenomics><Mice><Mice Mammals><Modern Man><Molecular><Molecular Mimicry><Monoclonal Antibodies><Moods><Multiple Sclerosis><Murine><Mus><NGS Method><NGS system><NIH><National Institutes of Health><Neuraxis><Neurologic><Neurological><Neurologist><Neuropathogenesis><Non-Polyadenylated RNA><Nucleic Acids><Out-patients><Outpatients><Pathogenesis><Pathogenicity><Patients><Pediatric Hospitals><Peripheral><Personality><PhIP-seq><Phage Display><Phage ImmunoPrecipitation Sequencing><Phenotype><Physiopathology><Plasma Cells><Plasmacytes><Play><Production><Proteome><Protocol><Protocols documentation><Pure Seminoma><RNA><RNA Gene Products><Resolution><Ribonucleic Acid><Rodent><Rodentia><Rodents Mammals><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 neurocognitive sequelae><SARS-CoV-2 neurological sequelae><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 antibody><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><San Francisco><Scientist><Self-Antigens><Seminoma><Sensitivity and Specificity><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Staining method><Stains><Steroid Compound><Steroids><Syndrome><Testing><Tissues><United States National Institutes of Health><Universities><Viral><Viral Antibodies><Viral Diseases><Virus Diseases><Work><Wuhan coronavirus><acute flaccid myelitis><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><adaptive immune response><adulthood><animal model development><anti-viral agents><anti-viral antibody><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><antibody-based immunity><antiviral antibody><antiviral compound><antiviral medication><antiviral therapeutic><autoimmune antibody><autoreactive antibody><base><bio-markers><biobank><biologic marker><biomarker><biorepository><brain tissue><cerebral spinal fluid><clinical care><clinical center><clinical phenotype><clinically actionable><cohort><complications due to COVID-19><corona virus disease 2019><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><cross reactivity><developmental><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><enroll><experiment><experimental research><experimental study><extracellular><hCoV19><host response><human CoV><human corona virus><human coronavirus><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoresponse><immunosuppressive activity><immunosuppressive function><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><insight><insular sclerosis><mAbs><men><men's><microbial><model of animal><model organism><monoclonal antibody production><nCoV><nCoV2><neural><neural mechanism><neural sequela in COVID-19><neuro post-acute sequelae of SARS-CoV-2><neurocognitive outcomes of coronavirus disease-19><neurocognitive symptoms and sequelae during COVID-19><neuroinflammation><neuroinflammatory><neurologic sequelae of COVID-19><neurological post-acute sequelae of SARS-CoV-2><neurological sequelae associated with SARS-CoV-2><neurological sequelae caused by SARS-CoV-2><neuromechanism><new CoV><new corona virus><new coronavirus><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel CoV><novel corona virus><novel coronavirus><overexpress><overexpression><pathogenic autoantibodies><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><plasmocyte><pleasure><post-COVID><post-COVID-19><post-acute CNS symptoms of SARS-CoV-2 infection><post-coronavirus disease 2019><programs><prospective><relating to nervous system><screening><self reactive antibody><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><spinal fluid><treatment strategy><viral detection><viral infection><virus detection><virus infection><virus-induced disease><youngster>