Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Division of Comparative Pathology, National Primate Research Center, Covington, Louisiana, USA.
Mol Cell Proteomics. 2023 Apr;22(4):100523. doi: 10.1016/j.mcpro.2023.100523. Epub 2023 Mar 3.
Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and the highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore, to better understand the impact of COVID-19 on the brain, we used mass-spectrometry-based proteomics with a data-independent acquisition mode to investigate cerebrospinal fluid (CSF) proteins collected from two different nonhuman primates, Rhesus Macaque and African Green Monkeys, for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe central nervous system (CNS) pathology. Our results indicated that CSF proteome changes after infection resolution corresponded with bronchial virus abundance during early infection and revealed substantial differences between the infected nonhuman primates and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals exhibited highly scattered data distributions compared to their corresponding controls indicating the heterogeneity of the CSF proteome change and the host response to the viral infection. Dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis, and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping these dysregulated proteins to the Human Brain Protein Atlas found that they tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It, therefore, appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.
神经系统表现是 COVID-19 最常报告的并发症之一。然而，由于 COVID-19 的组织样本稀缺且病原体具有高度传染性，我们对 COVID-19 的神经发病机制知之甚少。因此，为了更好地了解 COVID-19 对大脑的影响，我们使用基于质谱的蛋白质组学和数据非依赖性采集模式，研究了从两种不同的非人类灵长类动物（恒河猴和绿长尾猴）收集的脑脊液（CSF）蛋白质，以研究感染对神经系统的影响。这些猴子的肺部病理表现为轻度至中度，而中枢神经系统（CNS）病理为中度至重度。我们的结果表明，感染后 CSF 蛋白质组的变化与早期感染时支气管病毒的丰度相对应，并揭示了感染的非人类灵长类动物与其年龄匹配的未感染对照之间存在显著差异，这表明这些差异可能反映了中枢神经系统因子分泌的改变，以应对 SARS-CoV-2 诱导的神经病理学。我们还观察到感染动物的 CSF 蛋白质组变化数据分布高度分散，与相应的对照动物相比，这表明 CSF 蛋白质组变化和宿主对病毒感染的反应具有异质性。失调的 CSF 蛋白质更倾向于富集在与进行性神经退行性疾病、止血和先天免疫反应相关的功能途径中，这可能会影响 COVID-19 后的神经炎症反应。将这些失调的蛋白质映射到人类大脑蛋白质图谱上发现，它们倾向于富集在 COVID-19 后更频繁出现损伤的大脑区域。因此，推测 CSF 蛋白质的这种变化可以作为神经损伤的标志物，确定该过程中的重要调节途径，并可能揭示治疗靶点，以预防或减轻 COVID-19 后神经损伤的发展。
