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Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

ABSTRACT: PASC (Post-Acute Sequelae of COVID-19) involves many organs, including most prominently the central nervous system. Most studies of PASC in laboratory animals were performed in the context of mild disease, but higher PASC prevalence is observed in patients with severe disease. Here, to investigate the basis of chronic neurological disease, we infected mice with mouse-adapted SARS-CoV-2 that causes severe respiratory disease but does not infect the brain. We assessed long-term effects on olfactory and substantia nigra (SN) function. While anosmia resolved within a few days, we observed long term loss of tyrosine hydroxylase (TH) expression in the olfactory bulb glomeruli, indicating chronically altered function of olfactory sensory neurons. These changes were accompanied by increased inflammation suggesting the involvement of the host immune response in anosmia-related changes. We also observed decreased neurotransmitter expression in the substantia nigra (SN) accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. Microglia have been implicated in long term changes in SARS-CoV-2 infected mice and in human neurodegenerative disease. RNAseq analysis of mouse brain microglia isolated several months after infection demonstrated key roles for these cells in ongoing pathogenesis. Finally, we showed that early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titer and inflammation in the lung but did not prevent neurological abnormalities. Together these results show that these mice will be useful for probing the role of SARS-CoV-2 in the development of neurodegenerative disease, an aspect of disease not amenable to study in patients and that neurological PASC is not ameliorated by anti-viral therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE254984 | GEO | 2024/02/23

REPOSITORIES: GEO

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Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP. Transgenic hTH-GFP mice were treated with MPTP (4mg/kg) for either 2 or 10 days. Control mice were given an equal volume of saline for 10 days. Dopamine neurons from the substantia nigra and ventral tegmental areas of control and MPTP treated animals were laser captured. The RNA was isolated and processed for microarray hybridization. Each group had three biological replicates, for a total of 18 samples. Three each in the following: Control SN, Control VTA, 2 day MPTP SN, 2 day MPTP VTA, 10 day MPTP SN, 10 day MPTP VTA. Samples were log2 transformed and RMA normalized using Agilent Genespring 10.0 GX.

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Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

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