Targeting IDO in SARS-CoV2-induced Alzheimer's Disease progression

项目摘要/摘要 阿尔茨海默病(AD)是一种全国性的健康危机，影响着许多美国人的年总费用 预计到2050年将超过1万亿美元。阿尔茨海默病(AD)的风险是以下因素相互作用的结果 遗传和环境风险因素，随着年龄的增长，推动病理导致神经退行性变和 疾病发作。越来越多的流行病学证据表明，~80%的SARS-CoV2感染者， 和谁发展新冠肺炎，经历神经后遗症的共同病因为特征的 阿尔茨海默病，包括认知和神经精神缺陷。因此，很有可能 基于生物学和宿主的神经疾病(如阿尔茨海默病)的SARS-CoV2病因 对病毒的免疫反应。生物因素与中枢神经系统的过度活动交织在一起 新冠肺炎期间的炎症反应，影响中枢神经系统的功能状态。例如，双向 犬尿氨酸途径(KYN)及其受体异常与中枢神经系统炎症的关系 代谢物，如犬尿酸(KYNA)和喹啉酸(Quin)，存在于血液和脑脊液中 AD患者的体液；其水平与相关的神经和认知损害的严重程度相关 与艾滋病毒等病毒感染有关。重要的是，新冠肺炎患者KP代谢物的干扰和失调 与疾病严重程度相关，并由炎症诱导的吲哚胺2，3-双加氧酶(IDO)触发。这 提示SARS-CoV2对关键的KP代谢产物的调节失调和中枢神经系统炎症可能是其基础 中枢神经系统中的不适应变化加剧了AD的发展。因此，至关重要的是澄清 新冠肺炎期间SARS-CoV2诱导的KP异常与中枢神经系统炎症的相互作用 对AD疾病进展和神经发病机制的影响。这项提议的长期目标是 探讨感染性疾病的危险因素和神经发病机制 在SARS-CoV2神经后遗症的进展过程中AD的发生。使用老鼠适应的SARS-CoV2，我们将 解决我们的总体目标：描述SARS-CoV2中枢神经系统感染和进展过程中的KP失调 阿尔茨海默病的神经病理和神经认知能力下降与中枢神经系统免疫反应和 脑炎感染。中心假设是SARS-CoV2是发病和死亡的重要危险因素 AD的严重性，通过触发IDO活性从而失调外周和中枢神经系统的KP代谢物和 加剧随后的细胞因子风暴，从而加剧AD的神经病理。为了解决这一假设，我们 将1)区分感染SARS-CoV2后加剧的AD相关认知功能下降，2)描述SARS-CoV2 CoV2在AD中的神经病理、疾病负担以及宿主免疫和KP信号的双重激活，以及3) 阐明IDO在SARS-CoV2介导的AD发病和严重程度加重中的具体作用。这 提案将提供以免疫-KP为重点的方法，以确定SARS-CoV2对 阿尔茨海默病的神经退行性变过程。

Project Summary/Abstract Alzheimer’s disease (AD) is a national health crisis, affecting many Americans with total annual payments projected to be more than $1 trillion by 2050. The risk for Alzheimer’s disease (AD) is an interaction between inherited and environmental risk factors that, with age, drives pathology resulting in neurodegeneration and disease onset. Increasing epidemiological evidence indicates that ~80% of individuals infected with SARS-CoV2, and who develop Covid-19, experience neurological sequelae characterized by common etiological factors of Alzheimer’s disease, including cognitive and neuropsychiatric deficits. Therefore, there is a strong possibility in SARS-CoV2 causation of neurological conditions, such as Alzheimer’s disease, based on the biology and host immune responses to the virus. Biological factors intertwined with the overactivity of the CNS inflammatory response during Covid-19, impact the functional status of the CNS. For example, the bidirectional relationship between CNS inflammation and dysregulation of the kynurenine (KYN) pathway (KP) and its metabolites, such as kynurenic acid (KYNA) and quinolinic acid (QUIN), are found in the blood and cerebrospinal fluid of AD patients; and levels are correlated to severity of neurological and cognitive impairments associated with viral infections such as HIV. Importantly, disruption and dysregulation of KP metabolites in Covid-19 patients is correlated to disease severity and triggered by inflammation-induced indoleamine 2,3-dioxygenase (IDO). This indicates that dysregulation of critical KP metabolites and CNS inflammation by SARs-CoV2 may underlie maladaptive changes in the CNS that exacerbate the development of AD. Therefore, it is critical to elucidate the interplay between SARS-CoV2-induced KP dysregulation and CNS inflammation during Covid-19 and the impact on AD disease progression and neuropathogenesis. The long-term goal of this proposal is to investigate the infectious disease risk factors and mechanisms underlying the neuropathogenesis of AD during the progression of SARS-CoV2 neurological sequelae. Using mouse-adapted SARS-CoV2, we will address our overall objective: to delineate KP dysregulation during SARS-CoV2 CNS infection and progression of Alzheimer’s neuropathology and neurocognitive decline correlative to CNS immune responses and encephalitic infection. The central hypothesis is that SARS-CoV2 is a significant risk factor for the onset and severity of AD, by triggering IDO activity thereby dysregulating KP metabolites in the periphery and CNS and exacerbating the subsequent cytokine storm to exacerbate AD neuropathology. To address this hypothesis, we will 1) distinguish AD-related cognitive decline exacerbated following SARS-CoV2 infection, 2) delineate SARS- CoV2 neuropathology, disease burden, and dual activation of host immunity and KP signaling in AD, and 3) elucidate specific IDO contributions in SARs-CoV2-mediated exacerbation of AD onset and severity. This proposal will provide an immune-KP focused approach to identify SARS-CoV2 on the impact of neurodegenerative processes in AD.