miR-16-5p调控血管内皮细胞功能在梅毒螺旋体血行播散中的作用及机制

Treponema pallidum (Tp) infection could result in severe complications in multiple systems, includingcardiovascular, nervous and reproductive systems. The dissemination mechanism of Tp, especially the precise mechanism of disseminating from local lesions into the bloodstream,has not yet been elucidated. It is well known that angiogenesisis one of the major histopathological features of syphilis. We found that the.expression level of miR-16-5p in the peripheral blood of patients with syphilis is decreased, and that Tp could significantly downregulate miR-16-5p in human umbilical vein vascular endothelial cells (HUVECs).In addition, inhibition of miR-16-5p could increase the expression of VEGF and uPA, an angiogenesis factor and an enzyme facilitating the degradation of extracellularmatrix,in HUVECsand promote Tp invading the endothelial cell layer in a transwell assay.Therefore, we hypothesize that Tp infection coulddecreasethe expression of miR-16-5p in vascular endothelial cells, promote angiogenesis and increase vascular permeability, and finally lead to disseminating of Tp into the blood and multisysteminfection. To testthis hypothesis, we plan toexplore the functions of miR-16-5p inTp disseminationin clinical cases, cell model and rabbit syphilis model, and to analyze the molecular mechanismshow miR-16-5p regulatesproliferation,migration and extracellular matrix degradation of endothelial cells. This study could discover Tp dissemination mechanisms and mightfindnoveltargets for prevention and treatment of syphilis.

梅毒螺旋体（Tp）感染能引起心血管、神经、生殖等多个系统严重并发症，但其体内播散机制，尤其是从局部病灶突破血管内皮屏障进入血行播散的具体机制尚未阐明。研究发现血管内皮肿胀、增生是梅毒特征性病理表现之一。我们首次发现梅毒患者外周血中miR-16-5p下调，并在血管内皮细胞（HUVEC）中证实Tp可显著下调miR-16-5p，而抑制miR-16可增加VEGF（促血管生成）和uPA（促胞外基质降解）表达，并可促进Tp穿透内皮细胞层。因此，我们推测Tp感染有可能通过血管内皮细胞miR-16-5p表达下调，促进血管内皮细胞肿胀、血管通透性增加，使Tp进入血液，进而血行播散导致多系统受累。为检验这一假说，我们将从临床病例、细胞模型和梅毒兔模型3个层次，研究miR-16-5p在Tp血行播散中的作用，解析miR-16-5p调控内皮细胞增殖，迁移及细胞外基质降解的分子机制，为梅毒的防治提供新靶点和理论依据。

梅毒是由梅毒螺旋体感染导致的能够造成多种脏器损伤的较严重性传播疾病。目前尚不清楚梅毒螺旋体如何从皮肤血行播散至全身。本项目前期发现miR-16-5p在梅毒患者血液中差异表达，通过生物信息学分析发现其可能调控能够促进血管生成的基因——uPA和VEGF。因而本项目研究梅毒螺旋体是否是通过调控miR-16-5p，影响uPA和VEGF表达，从而增加血管的生成，促进血性播散。研究结果发现Tp能够影响人原代成纤维细胞下调miR-16-5p并上调uPA和VEGF的表达，进而影响血管内皮细胞AKT信号的活化，促进血管的生成。综上，本项目发现Tp可能通过调控uPA和VEGF的表达，来降解胞外基质和促进血管生成，最终促进其播散。本项目的研究为梅毒播散机制提供了理论基础，为梅毒治疗提供了新的思路。