COVID‐19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain

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

Severe acute respiratory syndrome coronavirus 2 infection leads to Tau pathological signature in neurons

“…Indeed, neuroinflammation has been reported in COVID-19 patients, especially in those requiring hospital or intensive care unit treatment. Interestingly, several inflammatory mediators such as TNF-α, IL-1β, NF-κB, IL-6, and MHCII, along with Iba-1 and GFAP-positive cells, are AD biomarkers and are activated in COVID-19 ( 61–64 ). This suggests a possible common mechanism leading to the increasing risk of neurological diseases.…”

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model

“…Neurotropism of SARS-CoV-2 is still under debate. Several in vitro studies showed that the cells of the CNS, particularly astrocytes and neurons, support SARS-CoV-2 replication ( Bullen et al, 2020 ; Jacob et al, 2020 ; Ramani et al, 2020 ; Wang et al, 2021 ; Andrews et al, 2022 ; Crunfli et al, 2022 ; Roczkowsky et al, 2023 ). In contrast, viral RNA was either absent ( Khan et al, 2021 ; Lee et al, 2021 , 2022 ; Yang et al, 2021 ) or present in low levels in a subset of the autopsy brain samples from fatal COVID-19 patients ( Kantonen et al, 2020 ; Matschke et al, 2020 ; Puelles et al, 2020 ; Solomon et al, 2020 ; Meinhardt et al, 2021 ; Roczkowsky et al, 2023 ).…”

Current clinical findings of acute neurological syndromes after SARS‐CoV‐2 infection

“…20,21 Omicron and its successor variants can infiltrate the CNS through the olfactory bulb, they not only induce inflam-mation in neurons, microglial cells, and astrocytes but can also directly damage neuronal cells. [22][23][24][25][26] Indeed, the direct infection of neuronal cells has been highly recognized as a significant factor contributing to neurological complications associated with COVID-19. 27,28 Over time, an increasing number of novel variants, such as XBB and JN.1, continue to emerge, leading to a growing interconnectedness between the virus and human existence.…”

“…Emerging SARS‐CoV‐2 variants, particularly Omicron and its successors, demonstrate altered virological characteristics, notably an increased inclination for neurotropism and neurotoxicity compared with earlier strains 20,21 . Omicron and its successor variants can infiltrate the CNS through the olfactory bulb, they not only induce inflammation in neurons, microglial cells, and astrocytes but can also directly damage neuronal cells 22–26 . Indeed, the direct infection of neuronal cells has been highly recognized as a significant factor contributing to neurological complications associated with COVID‐19 27,28 .…”