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

COVID-19急慢性神经系统后遗症的体液免疫机制

基本信息

批准号：
10387637
负责人：
SAMUEL JEREMY PLEASURE
金额：
$ 62.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387637
关键词：
2019-nCoV Acute Adult Anatomy Animal Disease Models Animal Model Antibodies Antibody Repertoire Antigens Antiviral Agents Autoantibodies Autoantigens Autoimmune Autoimmune encephalitis Autoimmunity B-Lymphocytes Behavioral Assay Biological Assay Biological Markers Blood Brain COVID-19 COVID-19 complications COVID-19 patient Cells Cerebrospinal Fluid Child Chronic Clinical Clinical Management Clinical Research Collaborations Complex Data Detection Development Disease Encephalitis Encephalopathies Enrollment Epitope Mapping Functional disorder General Hospitals Generations Goals Guillain Barré Syndrome Human Humoral Immunities Immune Immune response Immunofluorescence Immunologic Immunoprecipitation Immunosuppression Immunotherapy Infection Inflammation Inflammatory Infrastructure Infusion procedures Laboratories Laboratory Finding Maintenance Mass Spectrum Analysis Medical center Metagenomics Molecular Molecular Mimicry Monoclonal Antibodies Moods Multiple Sclerosis Mus Neuraxis Neurologic Neurologist Neuropathogenesis Nucleic Acids Outpatients Pathogenesis Pathogenicity Patients Pediatric Hospitals Peripheral Personality Phage Display Phage ImmunoPrecipitation Sequencing Phenotype Plasma Cells Play Production Proteome Protocols documentation RNA Resolution Rodent Role SARS-CoV-2 antibody SARS-CoV-2 infection SARS-CoV-2 spike protein Sampling San Francisco Scientist Seminoma Sensitivity and Specificity Stains Steroids Syndrome Testing Tissues United States National Institutes of Health Universities Viral Viral Antibodies Virus Diseases Work acute flaccid myelitis adaptive immune response animal model development base biobank brain tissue clinical care clinical center clinical phenotype clinically actionable cohort cross reactivity experimental study extracellular human coronavirus in vivo innovation insight men microbial monoclonal antibody production neuroinflammation neurologic sequelae of COVID-19 neuromechanism next generation sequencing novel novel coronavirus overexpression pathogenic autoantibodies pleasure post-COVID-19 programs prospective relating to nervous system screening treatment strategy viral detection

项目摘要

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

项目概要 COVID-19 与越来越多的外周和中枢神经系统并发症有关。已经清楚的是，这些综合征的一部分，包括急性坏死性脑病、类固醇- 反应性脑炎和吉兰-巴利综合征，可能是由于直接病毒神经侵袭和/或迫切需要对 SARS-CoV-2 引发的自身免疫进行前瞻性研究。 COVID-19 的慢性神经系统并发症，并确定哪些综合征起源于神经炎症。虽然针对 SARS-CoV-2 的抗病毒疗法仍在开发中，但自身免疫性中枢神经系统疾病可能会非常严重。因此，确定了部分 COVID-19 患者的生物标志物。自身免疫性中枢神经系统综合征尤其可能立即影响临床治疗。在过去的 8 年里，加州大学旧金山分校 (UCSF) 建立了一支由神经学家和基础科学家组成的独特跨学科团队成立的目的是开发和部署一种综合方法来快速识别微生物核酸、抗病毒药物与脑炎相关的抗体和抗神经抗体，明确意图发现和除了揭示疾病的基本机制之外，还验证临床上可行的生物标志物这些综合征的发病机制是这些努力的核心，是一个持续进行的患者队列。 NID（神经炎症疾病）队列，由疑似感染性或炎症性患者组成该队列现在有超过 1,400 名患者，由 UCSF 和周围其他中心的顾客转介。这个队列已经刺激了世界上第一个经过临床验证的脑脊髓的开发。液体宏基因组下一代测序测定，鉴定一种新型副肿瘤性自身免疫对男性精原细胞瘤具有重要意义的综合征以及肠道病毒脑脊液的鉴定在此，我们建议对现有的临床研究进行调整。和实验室基础设施来招募和调查 COVID-19 患者是否患有这一紧迫问题对于患有中枢神经系统炎症的持续神经系统后遗症，我们将合作开展这项工作。与美国国立卫生研究院、耶鲁大学以及加州大学旧金山分校医学中心的同事扎克伯格·圣弗朗西斯科总医院和加州大学旧金山分校贝尼奥夫儿童医院使用我们独特的临床和分子治疗。方法，我们将通过以下具体目标来研究这一假设：目标 1：表征患有急性和慢性神经系统疾病的 COVID-19 患者脑脊液中的自身抗体综合症目标 2：使用以下方法识别患有神经系统并发症的 COVID-19 患者的 CSF 特异性抗体库高分辨率 SARS-CoV-2 蛋白质组范围抗体分析目标 3：通过克隆生产单克隆抗体来阐明自身抗体的致病性扩增 COVID-19 患者脑脊液 B 细胞，以开发疾病动物模型