Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection

Abhishek Kumar Verma; Lu Tan; Noah Schuster; Skyler L Moye; Li-Chun Lin; Shea Lowery; Eazhisaivallabi Duraisami; Juan E Abrahante Lloréns; Qiang Qiu; Marco Hefti; David K Meyerholz; Mitchell C Coleman; C Ron Yu; Mark W Albers; Stanley Perlman

doi:10.1073/pnas.2530209123

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Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection

Journal article

Open access

Peer reviewed

Combination antiviral and anti-inflammatory therapy mitigates persistent neurological deficits in mice post SARS-CoV-2 infection

Abhishek Kumar Verma, Lu Tan, Noah Schuster, Skyler L Moye, Li-Chun Lin, Shea Lowery, Eazhisaivallabi Duraisami, Juan E Abrahante Lloréns, Qiang Qiu, Marco Hefti, …

Proceedings of the National Academy of Sciences - PNAS, Vol.123(2), e2530209123

01/13/2026

DOI: 10.1073/pnas.2530209123

PMCID: PMC12799161

PMID: 41499397

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https://pmc.ncbi.nlm.nih.gov/articles/PMC12799161/View

Open Access

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.

Animals

Anti-Inflammatory Agents - pharmacology

Anti-Inflammatory Agents - therapeutic use

Antiviral Agents - pharmacology

Antiviral Agents - therapeutic use

Brain - pathology

COVID-19 - complications

COVID-19 - pathology

COVID-19 - virology

COVID-19 Drug Treatment

Disease Models, Animal

Drug Therapy, Combination

Female

Humans

Male

Mice

Mice, Inbred C57BL

Nervous System Diseases - drug therapy

Nervous System Diseases - etiology

Nervous System Diseases - virology

SARS-CoV-2

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 Iowa
Lu Tan - University of Iowa
Noah Schuster - University of Iowa
Skyler L Moye - University of Iowa
Li-Chun Lin - University of Iowa, Psychological and Brain Sciences
Shea Lowery - University of Iowa
Eazhisaivallabi Duraisami - University of Iowa
Juan E Abrahante Lloréns - Pittsburgh Supercomputing Center
Qiang Qiu - Stowers Institute for Medical Research
Marco Hefti - University of Iowa
David K Meyerholz - University of Iowa
Mitchell C Coleman - University of Iowa
C Ron Yu - Case Western Reserve University
Mark W Albers - Harvard University
Stanley 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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