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

项目总结 新冠肺炎与越来越多的外周和中枢神经系统并发症有关。 很明显，这些症状的一部分，包括急性坏死性脑病，类固醇- 反应性脑炎和格林-巴利综合征可能是由于病毒直接侵入神经和/或 SARS-CoV-2引发的自身免疫。迫切需要对急性和非传染性疾病进行前瞻性调查 新冠肺炎的慢性神经系统并发症，并确定哪些症状是神经炎性的起源。 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非常严重 对免疫抑制有反应的。因此，为部分新冠肺炎患者识别生物标记物 尤其是自身免疫性中枢神经系统综合征会立即影响临床治疗。 在过去的8年里，加州大学旧金山分校一个由神经学家和基础科学家组成的独特的跨学科团队 成立的目的是开发和部署一种综合方法，以快速识别微生物核酸、抗病毒 与脑炎相关的抗体和抗神经抗体，明确的意图是发现和 除了揭示疾病的基本机制外，还验证临床上可操作的生物标志物 这些症状背后的发病机制。这些努力的核心是一个正在进行的患者队列，名为 NID(神经炎症性疾病)队列，由疑似感染或炎症性疾病的患者组成 脑炎。这个队列现在是由加州大学旧金山分校和周围其他中心的临床医生转介的1400名患者。 整个世界。这个队列已经刺激了第一个经过临床验证的脑脊液的开发。 流体元基因组下一代测序技术鉴定一种新的副肿瘤自身免疫 精原细胞瘤对男性的重要意义及肠道病毒脑脊液的鉴定 急性迟缓性脊髓炎患儿的抗体。在这里，我们建议将这项现有的临床研究 和实验室基础设施来招募和调查新冠肺炎患者是否 伴随着持续的神经系统后遗症有中枢神经系统炎症。我们将合作完成这项工作 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们 旧金山综合医院和加州大学旧金山分校贝尼奥夫儿童医院。利用我们独特的临床和分子技术 方法，我们将通过以下具体目标来研究这一假设： 目的1：新冠肺炎急慢性神经科患者脑脊液自身抗体的特征 证候 目的2：确定新冠肺炎神经系统并发症患者的脑脊液特异性抗体库 高分辨率SARS-CoV-2全蛋白质组抗体谱分析 目的3：通过生产克隆性自身抗体来阐明自身抗体的致病性 扩增新冠肺炎患者脑脊液B细胞可用于疾病动物模型的建立

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