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

摘要 大约有1650万人感染了SARS-CoV 2病毒，其中大约65万人（ 上升）死亡。虽然主要是呼吸道病毒，但临床观察似乎表明神经系统 参与。这些包括与CNS（头痛、意识模糊、癫痫发作、斯托克）、PNS（疼痛、嗅觉丧失， 味觉丧失）和肠神经系统（ENS，腹泻）。目前尚不完全清楚的是，SARS-CoV 2 病毒导致这些神经系统紊乱。我们也不知道对神经系统的影响是否会持续下去， 甚至可能在感染后变得明显我实验室以前的研究检查嗜神经性（H5 N1流感， 西方马脑炎病毒）和非嗜神经性（大流行性H1N1流感）已经表明，每一种都可以产生 CNS中的即时和/或延迟效应，包括诱导帕金森病中观察到的病理。有关 SARS-CoV-2，最近的一些研究，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%的人的病毒SARS-CoV-2 RNA和蛋白水平明显较低， 脑，虽然在这些研究中的每一个完整的细胞和定位图还没有被报道。而且， 已知在CNS中发现的病毒颗粒是否由于固有的嗜神经性而存在于细胞内，或仅存在于细胞内。 由于脑血管系统中的破坏而存在于CNS中。(i.e.,继发于脑血管损伤）。即使没有 向神经性，了解神经系统的变化是至关重要的，因为它是任何立即和/或延迟 效应可能是由神经系统外出现的功能失调信号（外周细胞因子风暴）引起的;然而， 影响神经元的功能和存活。为了解决这些悬而未决的问题，有两个具体目标： 提出了在具体目标1中，我们将根据经验确定SARS-CoV 2病毒的神经营养潜力 （USA-WA 1）在C57 BL/6 J小鼠和C57 BL/6 J小鼠的CNS、PNS和ENS中的整个自然感染期内， 表达人ACE 2受体（K18-hACE 2，B6.Cg-Tg（K18-ACE 2）2 Prlmn/J）的小鼠。我们亦会研究 在外周和大脑中引起炎症反应。在具体目标2中，我们将确定是否解决了SARS- CoV 2感染可使SNpc DA神经元对已显示诱导帕金森综合征的药剂（百草枯）敏感 和鱼藤酮），以及它是否会加剧α-突触核蛋白的传播和程度 病理这些目标和相关的实验将使我们能够直接确定亲神经性和免疫原性 SARS-CoV 2的潜力他们还将使我们能够确定这种病毒有可能使神经元敏感， 外源性损伤，如已经用一些其它呼吸道病毒证明的。了解这种流行性病毒 影响CNS，特别是基底神经节对于短期治疗和长期治疗都很重要 管理感染后的影响。此外，了解SARS-CoV 2在神经系统中的神经病理学后遗症， 神经系统将是必要的，为以后的研究，检查是否有治疗性干预（即疫苗或调节剂， 炎症反应）可以保护免受这种呼吸道感染的原发性和/或继发性神经系统影响。

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.