Synergistic Interactions of SARs-CoV2 and environmental toxicants in Experimental Parkinsonism

SARs-CoV2 与环境毒物在实验性帕金森病中的协同相互作用

• 批准号: 10316307
• 负责人: RICHARD J SMEYNE
• 金额: $ 42.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316307
• 关键词: 2019-nCoV; ACE2; Acute; Address; Affect; Ageusia; Anosmia; Autopsy; Basal Ganglia; Biological Assay; Blood; Brain; COVID-19; Cell Death; Cells; Cerebrovascular system; Cessation of life; Clinical; Confusion; Diarrhea; Disease; Dose; Encephalopathies; Enteric Nervous System; Experimental Parkinsonism; Headache; Human; Immune; Infection; Inflammation; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; K-18 conjugate; Maps; Methods; Microspheres; Modeling; Mus; Nervous system structure; Neurologic; Neurons; Neurotropism; Pain; Paraquat; Parkinson Disease; Parkinsonian Disorders; Pathology; Peripheral; Population; Process; Proteins; RNA; Reporting; Respiratory Tract Infections; Risk; Rotenone; SARS-CoV-2 infection; Secondary to; Seizures; Signal Transduction; Survivors; Symptomatic Parkinsonism; Symptoms; Syndrome; System; Therapeutic Intervention; Time; Toxic Environmental Substances; Tropism; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Western Equine Encephalitis Virus; Wild Type Mouse; alpha synuclein; astrogliosis; cerebrovascular; cytokine; cytokine release syndrome; dopaminergic neuron; environmental agent; experience; experimental study; immunogenic; nervous system disorder; nervous system infection; neuroinflammation; neuron loss; neurotropic; pandemic disease; particle; preclinical study; receptor; receptor binding; respiratory virus; response

ABSTRACT Approximately16.5 million people have been infected with the SARS-CoV2 virus with approximately 650,000 (and rising) deaths. While primarily a respiratory virus, clinical observations appear to demonstrate nervous system involvement. These include those associated with the CNS (headache, confusion, seizure, stoke), PNS (pain, anosmia, ageusia) and enteric nervous systems (ENS, diarrhea). What is not fully understood- at this time- is how the SARS-CoV2 virus produces these nervous system disorders. We also do not know if the impact(s) on the nervous system will persist, or possibly even become apparent, post infection. Previous studies in my lab examining neurotropic (H5N1 influenza, western equine encephalitic virus) and non-neurotropic (pandemic H1N1 influenza) have shown that each can produce immediate and/or delayed effects in the CNS, including induction of pathologies seen in Parkinson’s disease. Related to SARs-CoV2, a number of recent studies, using autopsy material has examined the localization of SARS-CoV-2 virus in the brain. From these studies, approximately 36% had apparently low levels of viral SARS-CoV-2 RNA and protein in brain, although in each of these studies a complete cellular and localization map have not been reported. Also, it is not known if the viral particles found in the CNS were present intracellularly due to inherent neurotropism or were only present in the CNS due to breaches in the cerebral vasculature. (i.e., secondary to cerebrovascular damage). Even without neurotropism, an understanding of changes in the nervous system are critical since it is that any immediate and/or delayed effects may result from dysfunctional signals (peripheral cytokine storms) that arise outside of the nervous system; yet impact the function and, perhaps, survival of neurons. To address these unanswered questions, two specific aims are proposed. In Specific Aim 1, we will empirically determine the neurotropic potential of the SARS-CoV2 virus (USA-WA1) throughout its natural period of infection in the CNS, PNS and ENS in C57BL/6J mice and C57BL/6J mice expressing a human ACE2 receptor (K18-hACE2, B6.Cg-Tg(K18-ACE2)2Prlmn/J). We will also examine the induced inflammatory response in the periphery and brain. In Specific Aim 2, we will determine if resolved SARS- CoV2 infection can sensitize SNpc DA neurons to agents that have been shown to induce parkinsonism (paraquat and rotenone) in mice and humans as well as if it can exacerbate the spread and extent of alpha-synuclein pathology. These aims and associated experiments will allow us to directly determine the neurotropic and immunogenic potential of SARS-CoV2. They will also allow us to determine this virus has the potential to sensitize neurons to exogenous insults as has been demonstrated with some other respiratory viruses. Understanding if this pandemic virus affects the CNS and in particular, the basal ganglia is important for both short term treatment as well as longer-term management of post infection effects. Additionally, understanding the neuropathological sequalae of SARS-CoV2 on the nervous system will be necessary for later studies examining if a therapeutic intervention (i.e. vaccine or modulator of inflammatory response) can protect against primary and/or secondary nervous system effects of this respiratory infection.

抽象的 大约 1650 万人感染了 SARS-CoV2 病毒，其中大约 65 万人（以及 虽然主要是呼吸道病毒，但临床观察似乎表明神经系统病毒。 这些包括与中枢神经系统（头痛、精神错乱、癫痫发作、中风）、PNS（疼痛、嗅觉丧失、 目前尚未完全了解 SARS-CoV2 是如何传播的。 我们也不知道病毒对神经系统的影响是否会持续存在。 或者甚至可能在感染后变得明显，我的实验室之前的研究检查了神经性（H5N1 流感， 西方马脑炎病毒）和非神经嗜性病毒（大流行性 H1N1 流感）已表明每种病毒都可以产生 对中枢神经系统的直接和/或延迟影响，包括诱发帕金森病相关的病理。 SARs-CoV2，最近的一些研究使用尸检材料检查了 SARS-CoV-2 病毒在 从这些研究来看，大约 36% 的人大脑中病毒 SARS-CoV-2 RNA 和蛋白质的水平明显较低。 大脑，尽管在每一项研究中都没有报道完整的细胞和定位图。 已知中枢神经系统中发现的病毒颗粒是否由于固有的向神经性而存在于细胞内，或者仅存在于细胞内 由于脑血管系统破裂而存在于中枢神经系统中（即继发于脑血管损伤）。 向神经性，对神经系统变化的理解至关重要，因为任何立即和/或延迟的变化 影响可能是由神经系统外部出现的功能失调信号（外周细胞因子风暴）引起的； 为了解决这些悬而未决的问题，我们有两个具体目标。 在具体目标 1 中，我们将凭经验确定 SARS-CoV2 病毒的神经营养潜力。 (USA-WA1) 在 C57BL/6J 小鼠和 C57BL/6J 的 CNS、PNS 和 ENS 中的整个自然感染期 我们还将检查表达人类 ACE2 受体（K18-hACE2、B6.Cg-Tg(K18-ACE2)2Prlmn/J）的小鼠。 在具体目标 2 中，我们将确定 SARS 是否已得到缓解。 冠状病毒感染可以使 SNpc DA 神经元对已被证明可诱发帕金森病的药物（百草枯 和鱼藤酮）在小鼠和人类中以及它是否会恶化 α-突触核蛋白的传播和范围 这些目标和相关实验将使我们能够直接确定神经营养性和免疫原性。 它们还将使我们能够确定这种病毒具有使神经元敏感的潜力。 正如一些其他呼吸道病毒所证明的那样，了解这种大流行病毒是否会造成外源性损害。 影响中枢神经系统，特别是基底神经节对于短期治疗和长期治疗都很重要 此外，了解 SARS-CoV2 的神经病理学后遗症。 神经系统对于以后的研究是必要的，以检查治疗干预措施（即疫苗或调节剂） 炎症反应）可以防止这种呼吸道感染的初级和/或次级神经系统影响。

项目成果

COVID-19 Infection Enhances Susceptibility to Oxidative Stress-Induced Parkinsonism.

• DOI: 10.1002/mds.29116
• 发表时间: 2022-07
• 期刊: MOVEMENT DISORDERS
• 影响因子: 8.6
• 作者: Smeyne, Richard J.;Eells, Jeffrey B.;Chatterjee, Debotri;Byrne, Matthew;Akula, Shaw M.;Sriramula, Srinivas;O'Rourke, Dorcas P.;Schmidt, Peter
• 通讯作者: Schmidt, Peter