Affiliation:
1. Department of Medicine University of Alberta Edmonton AB USA
2. Department of Cell Biology University of Alberta Edmonton AB USA
3. Li Ka Shing Institute of Virology University of Alberta Edmonton AB USA
4. Department of Medical Microbiology & Immunology University of Alberta Edmonton AB USA
5. Department of Pathology University of Calgary Calgary AB USA
6. Department of Laboratory Medicine & Pathology University of Alberta Edmonton AB USA
7. Department of Neuroscience University of Montreal, and CHUM Montreal QC Canada
Abstract
ObjectivePeroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection using a multiplatform strategy.MethodsBrain tissues from coronavirus disease 2019 (COVID‐19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS‐CoV‐2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT‐qPCR), and immunodetection methods.ResultsSARS‐CoV‐2 RNA was detected in the CNS of 4 patients with COVID‐19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID‐19 showed induction of pro‐inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM‐CSF and IL‐18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11β, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID‐19 compared to ODC patients (p < 0.05). SARS‐CoV‐2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post‐infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post‐infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS‐CoV‐2 infected animals (p < 0.05).InterpretationCOVID‐19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS‐CoV‐2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post‐acute sequelae of COVID‐19. ANN NEUROL 2023;94:531–546
Funder
Canadian Institutes of Health Research
Subject
Neurology (clinical),Neurology
Cited by
5 articles.
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