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

点击翻译按钮获取中文摘要

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.