The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation.
The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation.
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DOI：
10.1186/s12974-023-02711-2
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发表时间：
2023-02-09
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
COVID-19患者可能有多种神经系统症状，但中枢神经系统（CNS）在COVID-19中的主动参与仍不清楚。虽然对具有COVID-19神经系统表现的患者进行的常规脑脊液（CSF）分析通常显示没有或仅显示轻度炎症，但关于COVID-19患者CSF中炎症介质的更详细数据很少。我们研究了COVID-19患者（n = 38）配对CSF和血清样本中的炎症反应。单纯疱疹病毒性脑炎（HSVE，n = 10）和非炎症，非神经退行性神经系统疾病（n = 28）的患者作为对照。我们使用蛋白质组学、酶联免疫测定和半定量细胞因子阵列来表征炎症蛋白。用基于细胞的测定和天然组织染色进行自身抗体筛选。进行长链非编码RNA和环状RNA的RNA测序以研究转录组。单一蛋白水平的蛋白质组学和随后的途径分析显示，与HSVE患者相比，COVID-19患者的CSF中存在类似但强烈减弱的炎症变化，例如，载脂蛋白和细胞外基质蛋白的下调。补体系统、丝氨酸蛋白酶抑制剂蛋白途径和其他蛋白质（包括糖蛋白α-2和α-1酸）的蛋白质上调。重要的是，白细胞介素-6、白细胞介素-16和CXCL 10 CSF/血清指数的计算表明，这些炎症介质从体循环到达CSF，而不是在CNS内产生。抗体筛选显示没有病理水平的已知神经元自身抗体。当将COVID-19患者分为有和没有细菌重叠感染的患者时（如降钙素原水平升高所示），细菌重叠感染患者的炎症标志物显著（p < 0.01）更高。CSF中的RNA测序揭示了101种包含信使RNA的线性RNA，以及两种circRNA在COVID-19中与非神经炎症对照和神经退行性患者相比显著差异表达。我们的研究结果可以解释尽管存在SARS-CoV 2感染相关的神经症状，但常规CSF检测时没有鞘内炎症体征。CSF中血液来源的炎症介质与神经系统COVID-19和COVID-19后症状的相关性值得进一步研究。在线版本包含补充材料，可通过10.1186/s12974-023-02711-2获得。
Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p < 0.01) higher in those with bacterial superinfection. RNA sequencing in the CSF revealed 101 linear RNAs comprising messenger RNAs, and two circRNAs being significantly differentially expressed in COVID-19 than in non-neuroinflammatory controls and neurodegenerative patients. Our findings may explain the absence of signs of intrathecal inflammation upon routine CSF testing despite the presence of SARS-CoV2 infection-associated neurological symptoms. The relevance of blood-derived mediators of inflammation in the CSF for neurological COVID-19 and post-COVID-19 symptoms deserves further investigation. The online version contains supplementary material available at 10.1186/s12974-023-02711-2.
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影响因子：
9.3
作者：
Jarius S;Pache F;Körtvelyessy P;Jelčić I;Stettner M;Franciotta D;Keller E;Neumann B;Ringelstein M;Senel M;Regeniter A;Kalantzis R;Willms JF;Berthele A;Busch M;Capobianco M;Eisele A;Reichen I;Dersch R;Rauer S;Sandner K;Ayzenberg I;Gross CC;Hegen H;Khalil M;Kleiter I;Lenhard T;Haas J;Aktas O;Angstwurm K;Kleinschnitz C;Lewerenz J;Tumani H;Paul F;Stangel M;Ruprecht K;Wildemann B;in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry
通讯作者：
in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry
DOI：
10.1016/s1474-4422(20)30308-2
发表时间：
2020-11
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Matschke J;Lütgehetmann M;Hagel C;Sperhake JP;Schröder AS;Edler C;Mushumba H;Fitzek A;Allweiss L;Dandri M;Dottermusch M;Heinemann A;Pfefferle S;Schwabenland M;Sumner Magruder D;Bonn S;Prinz M;Gerloff C;Püschel K;Krasemann S;Aepfelbacher M;Glatzel M
通讯作者：
Glatzel M
影响因子：
4.6
作者：
Jøntvedt Jørgensen M;Holter JC;Christensen EE;Schjalm C;Tonby K;Pischke SE;Jenum S;Skeie LG;Nur S;Lind A;Opsand H;Enersen TB;Grøndahl R;Hermann A;Dudman S;Muller F;Ueland T;Mollnes TE;Aukrust P;Heggelund L;Holten AR;Dyrhol-Riise AM
通讯作者：
Dyrhol-Riise AM
影响因子：
5.8
作者：
Ballman, KV;Grill, DE;Therneau, TM
通讯作者：
Therneau, TM
影响因子：
3.8
作者：
Koertvelyessy, Peter;Goihl, Alexander;Reinhold, Dirk
通讯作者：
Reinhold, Dirk