Wang Xiao-Tong, Xie Lin, Hu Yun-Ting, Zhao Yuan-Yi, Wang Ruo-Ying, Yan Ya, Zhu Xiao-Zhen, Liu Li-Li
Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Digestive Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Center of Clinical Laboratory, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Microb Pathog. 2025 Feb;199:107216. doi: 10.1016/j.micpath.2024.107216. Epub 2024 Dec 9.
Increasing evidence suggests that immune cell clearance is closely linked to cellular metabolism. Neurosyphilis, a severe neurological disorder caused by Treponema pallidum (T. pallidum) infection, significantly impacts the brain. Microglia, the innate immune cells of the central nervous system, play a critical role in neuroinflammation and immune surveillance. However, the inability of the nervous system to fully eliminate T. pallidum points to a compromised clearance function of microglia. This study investigates how T. pallidum alters the immune clearance ability of microglia and explores the underlying metabolic mechanisms. RNA sequencing (RNA seq), LC-MS metabolomics, and XFe96 Seahorse assays were employed to assess metabolic activity in microglial cells. Western blotting, qPCR, and immunofluorescence imaging were utilized to evaluate autophagy flux and extent of T. pallidum infections. Transcriptomic analysis revealed that T. pallidum alters the transcription expression of key glycolytic enzymes, including hexokinase 1 (HK1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), leading to significant metabolic dysregulation. Specifically, metabolomic analysis showed reduced levels of phosphoenolpyruvate and citrate, while lactate production was notably increased. Functional assays confirmed that T. pallidum impairs glycolytic activity in microglial, as evidenced by decreased glycolytic flux, glycolytic reserve capacity, and maximum glycolytic capacity. Moreover, our results indicate that HK2, a crucial glycolytic enzyme, is closely associated with the autophagy. T. pallidum infection inhibits HK2 expression, which in turn suppresses autophagic flux by reducing the formation of lysosome-associated membrane protein 2 (LAMP2) and disrupting autophagosome-lysosome fusion. These findings suggest that T. pallidum hijacks microglial metabolic pathways, specifically glycolysis, to evade immune clearance. By inhibiting the glycolytic enzyme HK2, T. pallidum modulates autophagy and enhances immune evasion, providing a novel insight into the pathogenesis of neurosyphilis. This study paves the way for further investigations into the role of metabolic reprogramming in the immune escape mechanisms of T. pallidum.
越来越多的证据表明，免疫细胞清除与细胞代谢密切相关。神经梅毒是一种由梅毒螺旋体感染引起的严重神经系统疾病，会对大脑产生重大影响。小胶质细胞作为中枢神经系统的固有免疫细胞，在神经炎症和免疫监视中发挥着关键作用。然而，神经系统无法完全清除梅毒螺旋体表明小胶质细胞的清除功能受损。本研究调查了梅毒螺旋体如何改变小胶质细胞的免疫清除能力，并探索其潜在的代谢机制。采用RNA测序（RNA seq）、液相色谱 - 质谱代谢组学和XFe96 Seahorse分析来评估小胶质细胞中的代谢活性。利用蛋白质免疫印迹法、定量聚合酶链反应和免疫荧光成像来评估自噬通量和梅毒螺旋体感染程度。转录组分析表明，梅毒螺旋体改变了关键糖酵解酶的转录表达，包括己糖激酶1（HK1）、己糖激酶2（HK2）和乳酸脱氢酶A（LDHA），导致显著的代谢失调。具体而言，代谢组学分析显示磷酸烯醇丙酮酸和柠檬酸水平降低，而乳酸生成显著增加。功能分析证实，梅毒螺旋体损害小胶质细胞中的糖酵解活性，糖酵解通量、糖酵解储备能力和最大糖酵解能力降低证明了这一点。此外，我们的结果表明，关键糖酵解酶HK2与自噬密切相关。梅毒螺旋体感染抑制HK2表达，进而通过减少溶酶体相关膜蛋白2（LAMP2）的形成和破坏自噬体 - 溶酶体融合来抑制自噬通量。这些发现表明，梅毒螺旋体劫持小胶质细胞代谢途径，特别是糖酵解，以逃避免疫清除。通过抑制糖酵解酶HK2，梅毒螺旋体调节自噬并增强免疫逃逸，为神经梅毒的发病机制提供了新的见解。本研究为进一步研究代谢重编程在梅毒螺旋体免疫逃逸机制中的作用铺平了道路。
