Abstract
Objective: 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.
Methods: 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.
Results: 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.
Interpretation: 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.
【초록키워드】 SARS-CoV-2, Exosome, Mitochondria, Biomarker, Biomarkers, sodium, Human, Extracellular vesicles, Protein, nucleocapsid, therapeutic, Neuropsychiatric, plasma, long-COVID, Central nervous system, extracellular vesicle, PASC, Astrocyte, trials, calcium, mechanism, marker, SARS-CoV-2 proteins, manifestation, ANN, mitochondrial, therapeutic trials, respiratory chain, Frame, calcium channel, subunit, transmembrane, healthy controls, S1 protein, acute COVID-19, SARS-CoV-2 protein, SARS-CoV-2 N, leucine, Complex I, SARS-CoV-2 S1, CD81, controls, Cell, 12S rRNA, anion, complex III, Humanin, LETM1, N-methyl-D-aspartate, N-methyl-D-aspartate receptor, VDAC1, was used, significantly, resolved, quantified, MCU, 【제목키워드】 COVID-19, SARS-CoV-2,