Brain pathophysiology in SARS-CoV-2 disease

目前新冠肺炎大流行背后的SARS-CoV-2病毒不仅影响周围组织，它还 目标是大脑，导致微血管损伤、微出血和神经症状。这个 SARS-CoV-2的内化是由病毒刺突蛋白与血管紧张素转换结合启动的 酶2(ACE2)位于宿主细胞膜上，包括遍布大脑毛细血管的内皮细胞。 ACE2与病毒一起内化，从而导致ACE2缺乏状态。ACE2是一个关键成员 肾素-血管紧张素系统(RAS)。这种酶分解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、促炎和促血栓形成的影响 血管紧张素1型受体(AT1Rs)过度活跃。用AT1R拮抗剂阻断AT1R可保护小鼠免受 血管紧张素转换酶2缺乏所致的行为障碍。脂多糖(LPS)可引起小胶质细胞活化和 神经细胞丢失，被广泛用作神经炎症的实验模型。脑部病理生理学 脂多糖诱导的病毒感染与SARS-CoV-2感染有许多相似之处。我们假设在以下条件下 降低ACE2(即，ACE2基因敲除小鼠或感染SARS-CoV-2的仓鼠)，AT1R活性上调 微血管系统。在炎症性侮辱(例如，内毒素或SARS-CoV-2)存在的情况下，AT1Rs促进 促炎症和促血栓信号通路在微血管中的内皮功能障碍 导致血脑屏障损伤。随之而来的是认知缺陷和焦虑增加。我们将对此进行全面测试 通过以下具体目标进行假设：确定促进伤害的机制(目标1)和 (目标2)RAS的保护性手臂，在动物模型中调节大脑的病理生理 神经炎症和新冠肺炎。(目标3)确定生物性行为影响的潜在机制 和年龄在脂多糖和SARS-CoV-2诱导的脑病理生理中的作用。研究RAS在大脑中的机制 将为正在进行的和未来治疗脑损伤的治疗方法的临床试验提供洞察力 新冠肺炎等神经炎性疾病。此外，将重点放在影响的潜在机制上 生物学性别和年龄对神经炎症和新冠肺炎模型微血管病理生理学的影响 这将有助于解释为什么男性性别和年龄是新冠肺炎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.