Cerebrospinal fluid quantitative proteomic reveals potential mechanisms and biomarker candidates of children with bacterial meningitis complicated by neurological complications.

IF 3.3 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS
Binglin Jian, Jing Wei, Liang Zhu, Lingyun Guo, Bing Hu, Yue Xie, Tianming Chen, Bing Liu, Wanrong Li, Jidong Du, Linlin Liu, Xixi Zhang, Wei Sun, Zhengguang Guo, Kaihu Yao, Lulu Jia, Gang Liu
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引用次数: 0

Abstract

Background: Bacterial meningitis complicated by neurological complications (BMN) is a major cause of poor outcomes and mortality among children with bacterial meningitis. So far, the host-related mechanisms and diagnostic biomarkers of BMN and bacterial meningitis without neurological complications (BM) remain poorly understood and limited.

Methods: We implemented a two-stage cerebrospinal fluid (CSF) quantitative proteomics study involving three groups: children with BMN, BM, and diseases not involving the central nervous system(Ctrl). Initially, in the discovery cohort, data-independent acquisition (DIA) mass spectrometry was used for proteomic profiling on 242 CSF samples (77 BMN, 52 BM, and 113 Ctrl). Differentially expressed proteins (DEPs) were identified among the BMN/Ctrl, BM/Ctrl, and BMN/BM groups, followed by an analysis of their functional enrichment. Next, the parallel reaction monitoring (PRM) method was used to validate the essential DEPs identified during the DIA phase in a validation cohort of 196 subjects (94 BMN, 47 BM, and 55 Ctrl). Subsequently, the validated DEPs were further filtered to construct a PRM-based machine learning model that distinguishes between BMN and BM.

Results: A total of 1376 DEPs were identified in BM/Ctrl (757 upregulated, 619 downregulated), 1295 in BMN/Ctrl (745 upregulated, 550 downregulated), and 356 in BMN/BM(60 upregulated, 296 downregulated), respectively. The functional results indicate that the upregulated DEPs were primarily enriched in immunity, inflammation, complement, and phagocytosis in BMN/Ctrl and BM/Ctrl. Immunoglobulin production, phagocytosis, and the classical pathway of complement activation were further upregulated in BMN/BM. The downregulated DEPs are primarily enriched in cell adhesion, nervous system function, and synapses in BMN/Ctrl and BM/Ctrl; some were further enriched in BMN/BM. In addition, some of the innate immunity, translation, signal transduction, nervous system, and redox processes were mainly downregulated in BMN/BM. The PRM successfully verified 22 significant DEPs. Among them, UAB1, MTPN, ARHGDIB, IGHG3, and AMBP could be combined to distinguish BMN from BM, achieving an AUC of 0.998 in the training set and 0.824 in the validation set.

Conclusions: This study identified distinct CSF protein expression profiles in children with BMN, BM, and Ctrl, potentially enhancing our understanding of the molecular mechanisms underlying bacterial meningitis. These protein signatures help us distinguish bacterial meningitis from the Ctrl group. Furthermore, selected biomarkers could support the differentiation between BMN and BM.

脑脊液定量蛋白质组学揭示了儿童细菌性脑膜炎并发神经系统并发症的潜在机制和生物标志物候选物。
背景:细菌性脑膜炎合并神经系统并发症(BMN)是细菌性脑膜炎儿童预后不良和死亡的主要原因。到目前为止,BMN和细菌性脑膜炎无神经系统并发症(BM)的宿主相关机制和诊断生物标志物仍然知之甚少和有限。方法:我们实施了一项两阶段脑脊液(CSF)定量蛋白质组学研究,涉及三组:BMN、BM和不涉及中枢神经系统疾病(Ctrl)的儿童。最初,在发现队列中,使用数据独立采集(DIA)质谱法对242份脑脊液样本(77份BMN, 52份BM和113份Ctrl)进行蛋白质组学分析。在BMN/Ctrl、BM/Ctrl和BMN/BM组中鉴定差异表达蛋白(DEPs),并分析其功能富集。接下来,采用平行反应监测(PRM)方法对196名受试者(94名BMN, 47名BM和55名Ctrl)在DIA阶段鉴定的基本dep进行验证。随后,对经过验证的dep进行进一步过滤,构建基于prm的机器学习模型,以区分BMN和BM。结果:在BM/Ctrl中共鉴定出1376个dep(757个上调,619个下调),在BMN/Ctrl中鉴定出1295个dep(745个上调,550个下调),在BMN/BM中鉴定出356个dep(60个上调,296个下调)。功能结果表明,上调的DEPs主要富集于BMN/Ctrl和BM/Ctrl的免疫、炎症、补体和吞噬功能。免疫球蛋白的产生、吞噬和补体激活的经典途径在BMN/BM中进一步上调。下调的DEPs主要富集于细胞粘附、神经系统功能和BMN/Ctrl和BM/Ctrl的突触;部分细胞进一步富集BMN/BM。此外,一些先天免疫、翻译、信号转导、神经系统和氧化还原过程在BMN/BM中主要下调。PRM成功验证了22个重要dep。其中,UAB1、MTPN、ARHGDIB、IGHG3和AMBP可以联合用于区分BMN和BM,在训练集和验证集的AUC分别为0.998和0.824。结论:本研究确定了BMN、BM和Ctrl患儿不同的脑脊液蛋白表达谱,潜在地增强了我们对细菌性脑膜炎分子机制的理解。这些蛋白质特征帮助我们区分细菌性脑膜炎和Ctrl组。此外,选定的生物标志物可以支持BMN和BM之间的区分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical proteomics
Clinical proteomics BIOCHEMICAL RESEARCH METHODS-
CiteScore
5.80
自引率
2.60%
发文量
37
审稿时长
17 weeks
期刊介绍: Clinical Proteomics encompasses all aspects of translational proteomics. Special emphasis will be placed on the application of proteomic technology to all aspects of clinical research and molecular medicine. The journal is committed to rapid scientific review and timely publication of submitted manuscripts.
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