Liu Zhaoping, Zhang Xiaohong, Lin Ting, Ding Xuan, Yu Han, Yao Jiangchen, Gao Ke, Wu Yimou, Zhao Feijun
Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, People's Republic of China.
MOE Key Lab of Rare Pediatric Diseases&Institute of Pathogenic Biology and Key Laboratory of Special Pathogen Prevention and Control of Hunan Province, Hengyang Medical College, University of South China, Hengyang City, 421001, People's Republic of China.
AMB Express. 2025 Aug 25;15(1):126. doi: 10.1186/s13568-025-01940-3.
Neurosyphilis (NS) is a chronic central nervous system infection caused by Treponema pallidum. Owing to its diverse clinical manifestations and the limited sensitivity of current diagnostic methods, NS is difficult to diagnose. Understanding the molecular mechanisms of NS and identifying reliable biomarkers are essential for improving diagnostic and therapeutic strategies. This study employed Mendelian randomization (MR) analysis to explore the causal relationships among protein ratio quantitative trait loci (rQTLs), cerebrospinal fluid (CSF) metabolites, and syphilis risk at various stages. The results revealed that several rQTLs, including CD46/TNFRSF14 and TBC1D23/TBC1D5, were closely associated with syphilis risk, whereas others, such as BANK1/HEXIM1 and GOPC/HEXIM1, exhibited protective effects. Mediation analysis further identified key CSF metabolites, such as N-acetyltaurine and bilirubin, as important mediators linking rQTLs and syphilis progression. Through integrated analysis of cis-proteins from rQTLs and transcriptomic data from CD4 + T-cells of NS patients, METAP2 was identified as a key biomarker in NS, with the potential mechanisms elucidated. Importantly, T. pallidum may inhibit CD4 + T-cell proliferation by modulating METAP2, thereby accelerating disease progression. These findings offer new insights into the pathogenesis of NS and highlight METAP2 as a potential biomarker, laying a foundation for improving diagnostic and therapeutic strategies.
神经梅毒（NS）是一种由梅毒螺旋体引起的慢性中枢神经系统感染。由于其临床表现多样且当前诊断方法的敏感性有限，神经梅毒难以诊断。了解神经梅毒的分子机制并确定可靠的生物标志物对于改进诊断和治疗策略至关重要。本研究采用孟德尔随机化（MR）分析来探讨蛋白质比率数量性状位点（rQTL）、脑脊液（CSF）代谢物与不同阶段梅毒风险之间的因果关系。结果显示，包括CD46/TNFRSF14和TBC1D23/TBC1D5在内的几个rQTL与梅毒风险密切相关，而其他一些如BANK1/HEXIM1和GOPC/HEXIM1则表现出保护作用。中介分析进一步确定关键的脑脊液代谢物，如N-乙酰牛磺酸和胆红素，是连接rQTL与梅毒进展的重要中介物。通过对来自rQTL的顺式蛋白和神经梅毒患者CD4 + T细胞的转录组数据进行综合分析，METAP2被确定为神经梅毒的关键生物标志物，并阐明了其潜在机制。重要的是，梅毒螺旋体可能通过调节METAP2抑制CD4 + T细胞增殖，从而加速疾病进展。这些发现为神经梅毒的发病机制提供了新见解，并突出了METAP2作为潜在生物标志物的作用，为改进诊断和治疗策略奠定了基础。
