Cerebral vascular pathology of COVID-19

摘要 由严重急性呼吸综合征冠状病毒2型引起的新冠肺炎 致命性肺炎和呼吸窘迫在世界范围内造成了毁灭性的发病率和死亡率。此外, 中枢神经系统(CNS)是SARS-CoV-2病毒的攻击目标，研究发现 新冠肺炎患者脑组织和脑脊液中存在SARS-CoV-2。新兴市场的传播越来越广 SARS-CoV-2变种，如Delta或Omicron，似乎是健康优势的结果，而不是 创始人效应和/或遗传漂移；因此，类似的趋势预计将在未来继续下去。而当 新冠肺炎的急性临床症状以呼吸窘迫为主，神经和脑血管疾病 症状在所谓的“长冠状病毒病”或慢性冠状病毒病中起着关键作用。然而，SARS的相互作用-- CoV-2与脑微血管系统以及它们如何易患缺血性中风在很大程度上尚不清楚。这个 目前的提案旨在通过关注SARS-CoV-2对大脑的影响来弥合这一知识差距 并通过关注感染对微血管的长期影响。这项提议是基于中央 SARS-CoV-2 S1蛋白影响脑微血管完整性并影响卒中的假说 脑微血管炎症反应和表观遗传失调的发育 正直。这一假设是新颖的，拟议的研究可能会产生独特的数据集。作为 由于大量的财政投资，我们完成了对转录本签名的RNA-Seq分析 SARS-CoV-2感染人脑微血管内皮细胞(HBMEC)所获得的数据允许 美国将确定几个基因和途径，这些基因和途径对SARS-CoV-2诱导的脑损伤最有意义 微血管病理学。这项提议是建立在这些结果的基础上的。具体地说，我们将探索表观遗传学的作用 SARS-CoV-2诱导的脑血管功能障碍、高炎症反应和缺血的调节因子 卒中。 SARS-CoV-2对脑血管的影响在很大程度上是未知的，这使得拟议的研究真正 创新。了解SARS-CoV-2诱导微血管破坏的潜在机制(S)可能会 提供药物干预的目标，以防止病毒进入大脑和毁灭性的 与新冠肺炎有关的脑血管病理，尤指与这种疾病的一种慢性形式有关。因此， 这项提案的结果将提供至关重要的和与治疗相关的信息 脑血管系统参与新冠肺炎的病理过程。

ABSTRACT COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. An increased spread of emerging SARS-CoV-2 variants, such as delta or omicron, appears to be the result of a fitness advantage rather than founder effects and/or genetic drift; therefore, similar trends are expected to continue in the future. While respiratory distress dominates acute clinical symptoms of COVID-19, neurological and cerebrovascular symptoms play a critical role in so called “long-COVID” or chronic COVID. However, the interactions of SARS- CoV-2 with the brain microvasculature and how they predispose to ischemic stroke are largely unknown. The current proposal aims to close this gap of knowledge by its focus on the impact of SARS-CoV-2 on brain microvessels and by focusing on a long-term impact of the infection. The proposal is based on the central hypothesis that SARS-CoV-2 S1 protein affects the integrity of the brain microvessels and affects stroke development via inflammatory responses and epigenetic dysregulation of cerebral microvascular integrity. This hypothesis is novel, and the proposed studies are likely to generate unique data sets. As the result of substantial financial investments, we completed RNA-Seq analyses of transcriptomics signatures of human brain microvascular endothelial cells (HBMEC) infected with SARS-CoV-2. The obtained data allowed us to identify several genes and pathways, which most significantly contribute to SARS-CoV-2-induced cerebral microvascular pathology. The proposal is built on these results. Specifically, we will explore the role of epigenetic regulators in SARS-CoV-2-induced cerebrovascular dysfunction, hyperinflammatory reactions, and ischemic stroke. The impact of SARS-CoV-2 on the cerebral vasculature is largely unknown, making the proposed studies truly innovative. Knowledge of the underlying mechanism(s) of SARS-CoV-2-induced microvascular disruption may provide targets for pharmacological intervention to protect against viral entry into the brain and devastating cerebrovascular pathologies associated with COVID-19 and, especially with a chronic form of this disease. Thus, the outcome of this proposal will provide critically important and therapeutically-relevant information on the involvement of the cerebrovasculature in COVID-19 pathology.