Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Intramural Research Program, National Institute on Aging, Biomedical Research Center, Baltimore, Maryland, USA.
Ann Neurol. 2022 Jun;91(6):772-781. doi: 10.1002/ana.26350. Epub 2022 Mar 30.
As SARS-CoV-2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous system proteins in living humans was used to investigate neuropathogenic mechanisms of long-COVID-19.
SARS-CoV-2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) were quantified in resolved acute COVID-19 without post-acute sequelae of SARS-CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.
NDEV and ADEV mean levels of SARS-CoV-2 S1 and nucleocapsid (N) proteins were higher in all PASC sub-groups than controls, but only N levels were higher in PASC with than without NP. Exosome marker CD81-normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, and neuroprotective MPs Humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were decreased significantly in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MPs voltage-dependent anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, whereas those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX) and leucine zipper EF-hand containing transmembrane 1 protein (LETM1) were decreased only in PASC with NP. ADEV levels of MCU and NCLX only were increased in PASC without and with NP.
Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 protein and MPs correlate with NP and may be biomarkers for long-COVID prognostics and therapeutic trials. ANN NEUROL 2022;91:772-781.
已知 SARS-CoV-2 可入侵神经细胞的线粒体，因此使用一种可在活体人类中定量检测中枢神经系统蛋白质的血浆系统，来研究长新冠的神经致病机制。
在无 SARS-CoV-2 后期后遗症的急性 COVID-19（acute COVID-19 without post-acute sequelae of SARS-CoV-2，PASC）、无神经精神表现的 PASC（PASC without neuropsychiatric manifestations，NP）、有 NP 的 PASC 以及健康对照者中，对富集的血浆神经元衍生细胞外囊泡（neuron-derived extracellular vesicles，NDEVs）和星形胶质细胞衍生的 EVs（astrocyte-derived EVs，ADEVs）中的 SARS-CoV-2 蛋白和线粒体蛋白（mitochondrial proteins，MPs）进行定量。
在所有 PASC 亚组中，NDEV 和 ADEV 的 SARS-CoV-2 S1 和核衣壳（nucleocapsid，N）蛋白的平均水平均高于对照组，但只有有 NP 的 PASC 中 N 蛋白的水平高于无 NP 的 PASC。与对照组相比，亚单位 6 的呼吸链复合物 I 和亚单位 10 的复合物 III、神经保护蛋白 Humanin 和线粒体开放阅读框 12S rRNA-c（mitochondrial open-reading frame of the 12S rRNA-c，MOTS-c）的 CD81 归一化的 NDEV 平均水平在有 NP 的 PASC 中显著降低，但在无 NP 的 PASC 中则没有。无 NP 和有 NP 的 PASC 中，NDEV 水平的电压依赖性阴离子选择性通道蛋白 1（voltage-dependent anion-selective channel protein 1，VDAC1）和 N-甲基-D-天冬氨酸受体 1（N-methyl-D-aspartate receptor 1，NMDAR1）降低，而线粒体钙单向转运蛋白（mitochondrial calcium uniporter，MCU）、钠/钙交换蛋白（sodium/calcium exchanger，NCLX）和亮氨酸拉链 EF 手跨膜 1 蛋白（leucine zipper EF-hand containing transmembrane 1 protein，LETM1）的 MPs 仅在有 NP 的 PASC 中降低。无 NP 和有 NP 的 PASC 中，ADEV 水平的 MCU 和 NCLX 仅升高。
异常的 NDEV 和 ADEV 水平的 SARS-CoV-2 N 和 S1 蛋白和 MPs 与 NP 相关，可能是长新冠预后和治疗试验的生物标志物。神经病学年鉴 2022；91：772-781。
