Viral and immune-mediated CNS pathology during SARS-CoV-2 infection

补充项目摘要 自2019年底出现以来，SARS-CoV-2已在全球蔓延，在24个月中导致550万人死亡 月份。本课题组发表的工作表明，新冠肺炎的发病机制具有以下特点 重叠的TH1、TH2和TH17反应以及不同的、改变疾病的自身抗体的存在 (AAB)。急性SARS-CoV-2感染后的康复程度各不相同，14-35%的患者报告说 恢复期持续或出现新症状，统称为新冠肺炎急性后遗症 (PASC或“Long COVID”)。虽然PASC影响多个器官，但PASC的一个显著特征包括 神经症状包括持续的疲劳、肌肉疼痛、失眠、精神迟缓和神志不清。 PASC‘)。尽管在其他严重病毒感染后持续症状是常见的，但PASC患者 在后遗症中表现出显著和独特的隆起，即使与对照组相比也是如此。在……里面 在家长R01提案中，我们概述了我们调查SARS-CoV-2脑炎潜力的目标(目标1)， CNS、呼吸道及SARS-CoV-2联合感染对小鼠疾病转归的影响 模型(AIM 2)，并测定新冠肺炎有神经症状患者的中枢神经系统反应(AIM 3)。该附录将这些研究扩展到COVID急性神经后遗症的调查。对这件事 最后，我们整理了来自4个独立的多地点队列的约500名PASC患者的血浆和血清样本，以确定 与神经PASC相关的AABS(Suppl.目标1.1)，在定义明确的队列中研究纵向AAB反应 患有或不患有神经PASC的患者，我们有关于他们急性COVID感染的大量数据 (补充。目标1.2)，并使用机器学习方法来识别神经PASC的生物标记物(Suppl。目标 1.3)。此外，虽然最初的拨款提案使用SARS-CoV-2感染来模拟神经疾病，但 作为小鼠直接感染病毒的结果，本补充材料采用正交法来了解1)如何 与患者神经症状相关的AAB通过以下途径促进PASC的神经症状 AAB移植小鼠神经PASC模型的建立目标2.1)，以及2)探索SARS-CoV如何- 2感染与宿主对自身免疫的遗传易感性协同作用，形成AAB，导致神经细胞- PASC(补充目标2.2)。拟议的研究是假设驱动的、创新的、高度跨学科的，并具有 有很强的潜力通过阐明PASC 急性后遗症的发病机制和相关机制的识别。

Supplement Project Summary Since its appearance in late 2019, SARS-CoV-2 has spread globally and resulted in 5.5 million deaths in 24 months. Our group’s published work has demonstrated that the pathogenesis of COVID-19 is characterized by overlapping TH1, TH2, and TH17 responses and the presence of diverse, disease-modifying autoantibodies (AAB). The extent of recovery following acute SARS-CoV-2 infection is varied, with 14-35% of patients reporting persistent or new symptoms during convalescence, collectively termed as post-acute sequelae of COVID-19 (PASC or “Long COVID”). While PASC affects multiple organs, a prominent feature of PASC includes neurological symptoms including unremitting fatigue, myalgia, insomnia, mental slowing, and confusion (‘Neuro- PASC’). Although persistent symptoms are common following other severe viral infections, PASC patients demonstrate significant and unique elevations in sequelae even when matched against comparator groups. In the parent R01 proposal, we outlined our goals to investigate the encephalitic potential of SARS-CoV-2 (Aim 1), to evaluate effects of CNS, respiratory and combination SARS-CoV-2 infection on disease outcomes in mouse models (Aim 2), and to determine the CNS responses in COVID-19 patients with neurological symptoms (Aim 3). The supplement extends these studies to investigation of post-acute neurologic sequelae of COVID. To this end, we have collated ~500 PASC patient plasma and sera samples from 4 separate, multisite cohorts to identify AABs that correlate with neuro-PASC (Suppl. Aim 1.1), study longitudinal AAB responses in a well-defined cohort of patients with or without neuro-PASC for which we have extensive data from their acute COVID infection (Suppl. Aim 1.2) and to use machine learning approaches to identify biomarkers of neuro-PASC (Suppl. Aim 1.3). In addition, while the original grant proposal uses SARS-CoV-2 infection to model neurological diseases as a result of direct virus infection in mice, this supplement takes an orthogonal approach to understand 1) how AAB that correlate with neurological symptoms in patients contribute to neurological symptoms of PASC through development of an AAB-transfer mouse model for neuro-PASC (Suppl. Aim 2.1), and 2) probe how SARS-CoV- 2 infection synergizes with host genetic predispositions towards autoimmunity to develop AAB that lead to neuro- PASC (Suppl. Aim 2.2). The proposed research is hypothesis-driven, innovative, highly interdisciplinary, and has a strong potential to inform the diagnosis, prevention, mitigation, and treatment of PASC through elucidating the pathogenesis of post-acute sequelae and the identification of associated mechanistic pathways.