COVID-19 会引起大脑中的神经炎症并抑制过氧化物酶体。

COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

机构信息

Department of Medicine, University of Alberta, Edmonton, AB, USA.

Department of Cell Biology, University of Alberta, Edmonton, AB, USA.

出版信息

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

DOI:10.1002/ana.26679

PMID:37190821

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.

摘要

目的

在导致神经功能障碍的多种病毒感染中，过氧化物酶体损伤发生在中枢神经系统（CNS）中。我们使用多平台策略研究了严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染期间宿主神经免疫反应和过氧化物酶体生物发生因子。

方法

使用液滴数字聚合酶链反应（ddPCR）、定量逆转录聚合酶链反应（RT-qPCR）和免疫检测方法，研究了 12 例 2019 年冠状病毒病（COVID-19）和 12 例其他疾病对照（ODC）患者的脑组织，以及感染临床变异 SARS-CoV-2 的原代人神经细胞和叙利亚仓鼠。

结果

在 4 名 COVID-19 患者的 CNS 中检测到 SARS-CoV-2 RNA，在脑干中检测到病毒蛋白（NSP3 和刺突）免疫检测。与 ODC 患者的 CNS 组织相比，COVID-19 患者的嗅球、脑干和大脑显示促炎转录物（IL8、IL18、CXCL10、NOD2）和细胞因子（GM-CSF 和 IL-18）的诱导（p<0.05）。与 ODC 患者相比，COVID-19 的 CNS 中过氧化物酶体生物发生因子转录物（PEX3、PEX5L、PEX11β 和 PEX14）和蛋白质（PEX3、PEX14、PMP70）受到抑制（p<0.05）。SARS-CoV-2 感染仓鼠后，在感染后第 4 天和第 7 天在嗅球中检测到病毒 RNA，而在感染后第 14 天感染动物的大脑中上调了炎症基因表达（p<0.05）。SARS-CoV-2 感染动物的大脑中 Pex3 转录水平以及过氧化氢酶和 PMP70 免疫反应性受到抑制（p<0.05）。