California National Primate Research Center

修订摘要： 新冠肺炎大流行对美国和国外的医疗保健系统构成了重大挑战。SARS-CoV-2感染后机体的系统性损害已成为与新冠肺炎严重程度相关的重要因素，不成比例地影响患有高血压、糖尿病和痴呆症等并存疾病的老年患者。除了呼吸道症状，新冠肺炎患者还会出现神经系统症状，从频繁的嗅觉丧失到罕见但严重的神经血管和神经炎性事件。这些神经症状不成比例地影响阿尔茨海默病(AD)患者，并可能导致先前与更快的神经退行性进展和更差的行为结果相关的临床情景。然而，新冠肺炎过程中脑的参与以及SARS-CoV-2与AD病理途径的相互作用机制尚不清楚。我们在这个项目中的长期目标是进一步了解神经病理如何导致新冠肺炎的复杂临床表现，以及SARS-CoV-2感染和AD如何在脆弱的患者中产生负面协同作用。这笔赠款的目的是研究SARSCoV-2在幼年和老年糖尿病动物感染急性期对大脑的短期影响，以及免疫治疗预防的可能保护作用。中心假设是SARS-CoV-2具有神经侵袭性和嗜神经性，它进入大脑，感染神经元，并可能感染中枢神经系统内的其他细胞，导致神经退化、炎症和有利于痴呆的脑环境。其基本原理是，其他人类冠状病毒具有神经侵袭性和嗜神经性，包括密切相关的SARS-CoV1，会对神经元和髓鞘造成直接损害，并引发神经炎症过程。此外，SARS-CoV-2进入受体ACE2此前已被认为与AD有关，其他冠状病毒感染已被报道可触发与神经退化有关的适应性细胞内级联反应。我们的特定目标将检验以下假设：(1)SARS-CoV-2具有神经侵袭性，嗜神经性，其感染脑细胞可引起神经元和髓鞘损伤；(2)SARS-CoV-2感染引发神经炎症和细胞因子释放，通过康复血浆和单克隆抗体等免疫治疗剂的预防治疗，可以影响大脑反应；(目的3)新冠肺炎和AD的神经病理途径通过调节ACE2和应激反应途径，在分子水平上直接相互作用。这一贡献意义重大，因为它将极大地促进我们对新冠肺炎病理的了解，为这一重大公共卫生问题开辟新的治疗和护理途径，同时也提供了必要的框架，以了解新冠肺炎的长期后果及其对AD病理的影响。这项拟议的研究具有创新性，它使用了一个高度翻译的非人类灵长类动物模型来揭示病毒感染的神经生物学方面。

Revised Abstract: The COVID-19 pandemic constitutes a significant challenge to health care systems in the United States and abroad. A systemic compromise of the organism following SARS-CoV-2 infection has emerged as an important factor associated with COVID-19 severity, disproportionally affecting older patients with comorbidities such as hypertension, diabetes, and dementia. In addition to respiratory symptoms, COVID-19 patients can present neurological symptoms, ranging from the frequent loss of smell to rare but severe neurovascular and neuroinflammatory events. These neurological symptoms disproportionally affect patients with Alzheimer’s disease (AD) and can potentially lead to clinical scenarios previously associated with faster neurodegenerative progression and worse behavioral outcomes. The involvement of the brain during COVID-19 and the mechanisms of interaction between SARS-CoV-2 and AD pathological routes, however, remain poorly understood. Our long-term goal in this project is to further our knowledge on how neuropathology may contribute to the complex clinical presentation of COVID-19 and how SARS-CoV-2 infection and AD can negatively synergize in vulnerable patients. The objective of this grant is to characterize the short-term effects of SARSCoV-2 in the brain during the acute stage of the infection in both young and aged diabetic animals, and a possible protective effect of immunotherapeutic prophylaxis. The central hypothesis is that SARS-CoV-2 is both neuroinvasive and neurotropic, accessing the brain and infecting neurons and potentially other cells within the CNS, leading to neurodegeneration, inflammation, and a brain environment conducive to dementia. The rationale is that other human coronaviruses are neuroinvasive and neurotropic, including the closely related SARS-CoV1, causing direct damage to neurons and myelin and triggering neuroinflammatory processes. Furthermore, the SARS-CoV-2 entry receptor ACE2 has been previously implicated in AD, and other coronavirus infections have been reported to trigger adaptive intracellular cascades linked to neurodegeneration. Our specific aims will test the following hypotheses: (Aim 1) SARS-CoV-2 is neuroinvasive, neurotropic, and its infection of brain cells causes neuronal and myelinic damage; (Aim 2) SARS-CoV-2 infection triggers neuroinflammation and cytokine release, and prophylactic treatment with immunotherapeutic agents, such as convalescent plasma and monoclonal antibodies, can affect the brain response; (Aim 3) COVID-19 and AD neuropathological routes interact directly at the molecular level through the regulation of ACE2 and stress response pathways. This contribution is significant as it will considerably advance our knowledge of COVID-19 pathology, opening new avenues of treatment and care for a major public health concern, while also providing the necessary framework to understand the long-term consequences of COVID-19 and its impact on AD pathology. The proposed research is innovative in its use of a highly translational non-human primate model to reveal the neurobiological aspects of viral infections.