Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

Verma et al., bioRxiv, doi:10.1101/2024.06.02.596989

Jun 2024

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Mouse study showing persistent neurological deficits after SARS-CoV-2 infection, and failure of nirmatrelvir and molnupiravir to prevent neurological damage.

Authors found decreased tyrosine hydroxylase expression in the olfactory bulb and substantia nigra, along with elevated neuroinflammation and microglia activation, months after infection. Behavioral tests revealed impaired motor function. Similar decreases in tyrosine hydroxylase were seen in the substantia nigra of deceased COVID-19 patients.

Early treatment with systemic antivirals nirmatrelvir and molnupiravir did not prevent neurological damage. Administering treatments directly to the respiratory mucosa, where viral replication initially occurs, may be important to minimize the risk of neurological damage.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

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Study covers molnupiravir and paxlovid.

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15. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Verma et al., 3 Jun 2024, USA, preprint, 10 authors. Contact: stanley-perlman@uiowa.edu.

This Paper Molnupiravir All

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

Abhishek Kumar Verma, Shea Lowery, Li-Chin Lin, Eazhisaivallabi Duraisami, Juan E Abrahante Lloréns, Qiang Qiu, Marco Hefti, C Ron Yu, Mark W Albers, Stanley Perlman, Stanley Perlman

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

Author's contributions The study was designed by SP and AKV. Experiments were conducted by AKV, SL, ED, LCL. AKV, MH, QQ, CRY, MWA and SP acquired and analyzed data. JE helped with RNAseq data analysis. LCL, MH provided reagents. Manuscript was initially prepared by AKV and SP. All of the authors revised and approved the final manuscript. Conflict of Interest The authors declare no conflict of interest directly related to this study. MWA is a cofounder and owns shares in Aromha, Inc. He has received in kind contributions from Eli Lilly and research

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