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Principal Investigator: RICHARD J SMEYNE
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2021
Award: $429,000
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <1,1'-dimethyl-4,4'-bipyridinium><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acute><Address><Affect><Ageusia><Anosmia><Assay><Autopsy><Basal Ganglia><Basal Nuclei><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Reticuloendothelial System><Brain><Brain Nervous System><COVID-19><COVID-19 infection><COVID-19 virus><COVID19><COVID19 infection><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Cephalalgia><Cephalgia><Cephalodynia><Cerebrovascular system><Cessation of life><Clinical><CoV-2><CoV2><Confusion><Confusional State><Cranial Pain><DA Neuron><Death><Diarrhea><Disease><Disorder><Dopamine neuron><Dose><Encephalon><Encephalopathies><Enteric Nervous System><Environmental Toxin><Experimental Parkinson Disease><Experimental Parkinsonism><Grippe><H1N1><H1N1 Virus><H5N1><H5N1 virus><Head Pain><Headache><Human><Immune><Immunes><Infection><Inflammation><Inflammatory Response><Influenza><Influenza A Virus, H1N1 Subtype><Influenza A Virus, H5N1 Subtype><Intracellular Communication and Signaling><K-18><K-18 conjugate><K18><K18 combination><MPTP-Induced Experimental Parkinsonism><Maps><Mental Confusion><Methods><Methyl Viologen><Mice><Mice Mammals><Microbeads><Microspheres><Modeling><Modern Man><Murine><Mus><NAC precursor><Nerve Cells><Nerve Unit><Nervous System><Nervous System Diseases><Nervous System Infectious Disorder><Nervous system structure><Neural Cell><Neurocyte><Neurologic><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological><Neurological Disorders><Neurons><Neurotropism><Non-Polyadenylated RNA><PARK1 protein><PARK4 protein><Pain><Painful><Paralysis Agitans><Paraquat><Parkinson><Parkinson Disease><Parkinson's disease><Parkinsonian><Parkinsonian Condition><Parkinsonian Diseases><Parkinsonian Disorders><Parkinsonian Syndrome><Parkinsonism><Parkinsons disease><Pathology><Peripheral><Population><Primary Parkinsonism><Process><Proteins><RNA><RNA Gene Products><Receptor Protein><Reporting><Respiratory Infections><Respiratory Tract Infections><Ribonucleic Acid><Risk><Rotenone><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SNCA><SNCA protein><Secondary Parkinsonism><Secondary to><Seizures><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Survivors><Symptomatic Parkinson Disease><Symptomatic Parkinsonism><Symptoms><Syndrome><System><Therapeutic Intervention><Time><Toxic Environmental Agents><Toxic Environmental Substances><Tropism><Vaccines><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><WEE Virus><WEEV><Western Equine Encephalitic Virus><Western Equine Encephalitis Virus><Western Equine Encephalomyelitis Virus><Wild Type Mouse><Wuhan coronavirus><a-syn><a-synuclein><alpha synuclein><alphaSP22><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><astrogliosis><avian influenza H5N1><avian influenza H5N1 virus><biological signal transduction><brain blood vessels><brain vasculature><cerebral blood vessel><cerebral vascular><cerebral vasculature><cerebro-vascular><cerebrovascular><cerebrovascular vessels><cerebrovasculature><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><cytokine><cytokine release syndrome><cytokine storm><dopaminergic neuron><environmental agent><environmental toxicant><experience><experiment><experimental research><experimental study><hCoV19><head ache><immunogenic><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><intervention therapy><loss of smell><nCoV2><necrocytosis><necropsy><nerve cell death><nerve cell loss><nervous system disorder><nervous system infection><neuroinflammation><neuroinflammatory><neurological disease><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neurotropic><non A-beta component of AD amyloid><non A4 component of amyloid precursor><olfactory loss><pandemic><pandemic disease><particle><postmortem><pre-clinical study><preclinical study><receptor><receptor binding><receptor bound><respiratory virus><response><viral infection><viral respiratory infection><virus infection><virus-induced disease><wildtype mouse><α-syn><α-synuclein>