COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain

A Roczkowsky; D Limonta; J P Fernandes; W G Branton; M Clarke; B Hlavay; R S Noyce; J T Joseph; N S Ogando; S K Das; M Elaish; N Arbour; D H Evans; K Langdon; T C Hobman; C Power

doi:10.1002/ana.26679

COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain

Ann Neurol. 2023 Sep;94(3):531-546. doi: 10.1002/ana.26679. Epub 2023 Jun 5.

Authors

A Roczkowsky¹, D Limonta^{2

3}, J P Fernandes⁴, W G Branton¹, M Clarke¹, B Hlavay¹, R S Noyce⁴, J T Joseph⁵, N S Ogando¹, S K Das⁶, M Elaish², N Arbour⁷, D H Evans⁴, K Langdon⁵, T C Hobman^{2

3

4}, C Power^{1

4}

Affiliations

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.

PMID: 37190821
DOI: 10.1002/ana.26679

Abstract

Objective: Peroxisome 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.

Methods: Brain 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.

Results: SARS-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).

Interpretation: COVID-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
COVID-19*
Humans
Neuroinflammatory Diseases
Peroxisomes
RNA, Viral
SARS-CoV-2

Substances

RNA, Viral

Grants and funding

A5555/CIHR/Canada