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 大约有1650万人感染了SARS-COV2病毒，约有65万人 崛起）死亡。虽然主要的呼吸道病毒，但临床观察似乎表明神经系统 参与。其中包括与CNS相关的（头痛，混乱，癫痫发作，Stoke），PNS（疼痛，厌食， AgeUsia）和肠神经系统（ENS，腹泻）。目前尚未完全理解的是SARS-COV2 病毒会产生这些神经系统疾病。我们也不知道对神经系统的影响是否会持续存在， 甚至可能变得显而易见，感染后。先前在我的实验室检查神经旋转的研究（H5N1影响力， 西方马脑脑病毒）和非神经性（大流行的H1N1影响）表明，每个人都可以产生 中枢神经系统中的直接和/或延迟作用，包括诱导帕金森氏病中的病理。与 SARS-COV2是许多最近的研究，使用尸检材料检查了SARS-COV-2病毒在 大脑。从这些研究中，大约36％的病毒SARS-COV-2 RNA和蛋白质的水平显然很低。 尽管在这些研究中，大脑尚未报告完整的细胞和定位图。另外，不是 知道中枢神经系统中发现的病毒颗粒是否由于遗传神经性神经或仅是细胞内存在还是仅是 由于脑脉管系统的呼吸而存在于中枢神经系统中。 （即，继发于脑血管损伤）。即使没有 神经性，对神经系统变化的理解至关重要，因为这是任何直接和/或延迟的 影响可能是由于神经系统外发生的功能失调信号（周围细胞因子风暴）所致。然而 影响功能，也许会影响神经元的生存。为了解决这些未解决的问题，两个具体的目标是 建议的。在特定的目标1中，我们将凭经验确定SARS-COV2病毒的神经性潜力 （USA-WA1）在CNS，PNS和C57BL/6J小鼠和C57BL/6J中的自然感染期间 表达人ACE2受体的小鼠（K18-HACE2，B6.CG-TG（K18-ACE2）2PRLMN/J）。我们还将检查 周围和大脑诱导的炎症反应。在特定目标2中，我们将确定是否已解决已解决的SARS- COV2感染可以将SNPC DA神经元感知到已显示出诱导帕金森主义的特工（Paraquat） 在小鼠和人类中）以及是否会加剧α-突触核蛋白的扩散和程度 病理。这些目的和相关的实验将使我们能够直接确定神经性和免疫原性 SARS-COV2的潜力。他们还将允许我们确定该病毒有可能感知神经元 如其他一些呼吸道病毒所证明的外源性侮辱。了解这种大流行病毒是否 影响中枢神经系统，尤其是基本神经节对于短期治疗以及长期 治疗后感染效应。另外，了解SARS-COV2的神经病理序列 神经系统将需要以后研究是否治疗干预（即疫苗或调节剂） 炎症反应）可以预防这种呼吸道感染的原发性和/或继发性神经系统作用。

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