Journal article
Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection
Proceedings of the National Academy of Sciences - PNAS, Vol.123(2), e2530209123
01/13/2026
DOI: 10.1073/pnas.2530209123
PMCID: PMC12799161
PMID: 41499397
Abstract
Post-acute sequelae of COVID-19 (PASC) encompasses persistent neurological disease, including olfactory and cognitive dysfunction. The basis for this dysfunction is poorly understood. Here, we report neurological dysfunction for at least 120 d postinfection in mice infected with a virulent nonneurotropic mouse-adapted SARS-CoV-2. Long after recovery from nasal infection, we observed diminished tyrosine hydroxylase expression in olfactory bulb glomeruli and in substantia nigra. Similar changes were observed in brains of COVID-19 deceased patients. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased proinflammatory cytokines, and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, similar to human neurodegenerative diseases. Treatment with antivirals (nirmatrelvir and molnupiravir) at the time of infection minimally prevented neurological abnormalities, consistent with patient data. In contrast, antivirals plus corticosteroids resulted in nearly complete recovery of neurological function. Remarkably, initiation of combined therapy even three days after infection improved outcomes. Together these results demonstrate that neurological dysfunction in SARS-CoV-2 infected mice resembles human neurodegenerative disease and indicate that minimizing inflammation early after SARS-CoV-2 infection may be critical for decreasing neurological PASC. The requirement for decreasing inflammation soon after infection may also explain why antiviral therapy has had inconsistent effects in patients.
Details
- Title: Subtitle
- Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection
- Creators
- Abhishek Kumar Verma - University of IowaLu Tan - University of IowaNoah Schuster - University of IowaSkyler L Moye - University of IowaLi-Chun Lin - University of Iowa, Psychological and Brain SciencesShea Lowery - University of IowaEazhisaivallabi Duraisami - University of IowaJuan E Abrahante Lloréns - Pittsburgh Supercomputing CenterQiang Qiu - Stowers Institute for Medical ResearchMarco Hefti - University of IowaDavid K Meyerholz - University of IowaMitchell C Coleman - University of IowaC Ron Yu - Case Western Reserve UniversityMark W Albers - Harvard UniversityStanley Perlman - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.123(2), e2530209123
- DOI
- 10.1073/pnas.2530209123
- PMID
- 41499397
- PMCID
- PMC12799161
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R01 AI129269 / NIAID NIH HHS P01 AI060699 / NIAID NIH HHS RF1 AG078297 / HHS | NIH | National Institute on Aging (NIA) R01 NS36592 / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
- Language
- English
- Date published
- 01/13/2026
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Psychological and Brain Sciences; Pathology; Iowa Neuroscience Institute; Orthopedics and Rehabilitation; Infectious Disease (Pediatrics)
- Record Identifier
- 9985116066202771
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