Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

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. Comparative gene analysis between Mock and 100dpi mouse brain CD11b+ cells