Cerebral vascular pathology of COVID-19

摘要 COVID-19由严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）引起， 致命性肺炎和呼吸窘迫在全世界造成了毁灭性的发病率和死亡率。此外，本发明还提供了一种方法， 中枢神经系统（CNS）是SARS-CoV-2的靶点， COVID-19患者脑和脑脊液中的SARS-CoV-2。新兴经济体的蔓延 SARS-CoV-2变异体，如delta或omicron，似乎是适应性优势的结果，而不是 创始人效应和/或遗传漂变;因此，预计今后将继续出现类似的趋势。而 呼吸窘迫是COVID-19、神经和脑血管疾病的主要急性临床症状 症状在所谓的“长期COVID”或慢性COVID中起关键作用。然而，SARS的相互作用- CoV-2与脑微血管系统的关系以及它们如何易患缺血性中风在很大程度上是未知的。的 目前的提案旨在通过关注SARS-CoV-2对大脑的影响来填补这一知识空白 微血管和关注感染的长期影响。该提案基于中央 假设SARS-CoV-2 S1蛋白影响脑微血管的完整性并影响中风 通过炎症反应和脑微血管表观遗传失调的发展 完整这一假设是新颖的，拟议的研究可能会产生独特的数据集。为 由于大量的财政投资，我们完成了转录组学签名的RNA-Seq分析， 人脑微血管内皮细胞（HBMEC）感染SARS-CoV-2。获得的数据允许 我们确定了几个基因和途径，这些基因和途径对SARS-CoV-2诱导的脑损伤最有意义。 微血管病理学该提案是建立在这些结果之上的。具体来说，我们将探讨表观遗传的作用， SARS-CoV-2诱导的脑血管功能障碍、炎症反应过度和缺血性 中风 SARS-CoV-2对脑血管的影响在很大程度上是未知的，使得拟议的研究真正 新颖啊了解SARS-CoV-2诱导微血管破坏的潜在机制可能 为药物干预提供靶点，以防止病毒进入大脑， 与COVID-19相关的脑血管病变，特别是与这种疾病的慢性形式相关的脑血管病变。因此，在本发明中， 该提案的结果将提供关于以下方面的至关重要和治疗相关的信息： 在COVID-19病理学中涉及血管系统。

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.