Brain pathophysiology in SARS-CoV-2 disease

SARS-CoV-2是当前COVID-19大流行的病毒基础，不仅影响外周组织，还 靶向大脑，引起微血管病变、微血管病变和神经系统表现。的 SARS-CoV-2的内在化是通过病毒刺突蛋白与血管紧张素转化酶结合而启动的。 酶2（ACE 2）在宿主细胞的膜上，包括整个脑毛细血管的内皮细胞。 ACE 2与病毒一起被内化沿着，从而导致ACE 2缺乏状态。ACE 2是一个关键成员 肾素-血管紧张素系统（RAS）。这种酶分解代谢八肽激素血管紧张素-[1-8] 从而保护细胞和组织免受血管收缩剂、促炎剂和促血栓形成剂的作用。 过度活跃的血管紧张素1型受体（AT 1 Rs）。用AT 1 R拮抗剂阻断AT 1 R可保护小鼠免受 ACE 2缺乏导致的行为障碍。脂多糖（LPS）引起小胶质细胞活化， 神经元细胞损失，并广泛用作神经炎症的实验模型。脑病理生理学 LPS诱导的SARS病毒感染与SARS-CoV-2感染有许多相似之处。我们假设在 降低的ACE 2（即，ACE 2敲除小鼠或SARS-CoV-2感染仓鼠），AT 1 R活性在 微血管系统在存在炎性损伤的情况下（即，LPS或SARS-CoV-2），AT 1 Rs促进 通过促炎和促血栓形成信号通路的微血管内皮功能障碍 导致血脑屏障损伤。随之而来的是认知缺陷和焦虑增加。我们将全面测试这一点 通过以下具体目标的假设：确定促损伤的机制（目标1）， RAS的保护性（目的2）臂，在动物模型中调节脑的病理生理学， 神经炎症和新冠肺炎(Aim 3）确定生物性别影响的潜在机制 和年龄在LPS和SARS-CoV-2诱导的脑病理生理学中的作用。研究大脑中的RAS机制 将为正在进行的和未来的治疗脑损伤的临床试验提供深入了解， COVID-19和其他神经炎症疾病。此外，关注影响的潜在机制 生物学性别和年龄对神经炎症和COVID-19模型中微血管病理生理学的影响 将揭示为什么男性性别和年龄是COVID-19严重程度的主要风险因素。

SARS-CoV-2, the virus underlying the current COVID-19 pandemic, not only affects peripheral tissues, it also targets the brain causing microvascular lesions, microhemorrhages and neurological manifestations. The internalization of SARS-CoV-2 is initiated by the binding of the virus spike protein to angiotensin converting enzyme 2 (ACE2) on the membrane of host cells including endothelial cells throughout cerebral capillaries. ACE2 is internalized along with the virus thereby leading to a state of ACE2 deficiency. ACE2 is a critical member of the renin-angiotensin system (RAS). This enzyme catabolizes the octapeptide hormone angiotensin-[1-8] thereby protecting cells and tissues from the vasoconstrictor, pro-inflammatory and pro-thrombotic effects of overactive angiotensin type 1 receptors (AT1Rs). Blocking AT1Rs with an AT1R antagonist protects mice from behavioral impairments due to ACE2 deficiency. Lipopolysaccharide (LPS) causes microglia activation and neuronal cell loss and is widely used as an experimental model of neuroinflammation. The brain pathophysiology induced by LPS shares many similarities with SARS-CoV-2 infection. We hypothesize that under conditions of reduced ACE2 (i.e., ACE2 knockout mice or SARS-CoV-2-infected hamsters), AT1R activity is upregulated in the microvasculature. In the presence of an inflammatory insult (i.e., LPS or SARS-CoV-2), AT1Rs promote endothelial dysfunction in the microvasculature through pro-inflammatory and pro-thrombotic signaling pathways leading to blood brain barrier injury. Deficits in cognition and increased anxiety ensue. We will test this overall hypothesis through the following specific aims: Determine the mechanisms of the pro-injury (Aim 1) and protective (Aim 2) arms of the RAS that regulate the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. (Aim 3) Determine the mechanisms underlying the effects of biological sex and age in the brain pathophysiology induced by LPS and SARS-CoV-2. Studying RAS mechanisms in the brain will provide insight into on-going and future clinical trials of therapeutics for treating brain injury associated with COVID-19 and other diseases of neuroinflammation. In addition, focusing on mechanisms underlying the effects of biological sex and age on microvasculature pathophysiology in models of neuroinflammation and COVID-19 will shed light into why male sex and age are major risk factors for COVID-19 severity.