Systemic Innate Immune Responses in Secondary Syphilis

描述（由申请人提供）：性病是由螺旋体病原体梅毒螺旋体引起的性传播疾病。这种疾病仍然不受控制，特别是在资源匮乏的地区，那里并不总是能够获得检测、治疗和适当的后续治疗。梅毒的特点是在最初感染的部位出现局部溃疡，到一系列慢性全身性炎症表现，如果不及时治疗，可导致严重并发症甚至死亡。无法培养这种细菌阻碍了人们对其发病机制的全面了解，特别是为什么螺旋体能够逃避免疫系统。因此，这里提出的研究旨在更好地描述这种免疫反应的性质，因为它发生在人类梅毒中。继发性梅毒患者的全身细胞先天免疫反应将是当前建议的重点。我们假设在继发性梅毒中，血液中存在的苍白t直接激活循环单核细胞和树突状细胞。为此，在特异性目标1中，我们将首先使用一种新的实时定量PCR方法确认螺旋体DNA存在于继发性梅毒患者的血液中；在特异性目标2中，我们将通过使用多参数四色流式细胞术和“实时”PCR （RT-PCR）来量化它们的促炎细胞因子基因表达信号，表征T. pallidum驱动的循环单核细胞和树突状细胞的免疫反应。补充的离体研究，旨在确定细菌对先天和适应性免疫细胞的特定成分的影响。从这两条平行的研究路线中，我们将对梅毒的发病机制有更深入的了解，可以沿着细胞和分子线进一步发展，并最终促进疫苗的开发。为了配合福格蒂国际中心减少国家间健康差距的使命，计划中的活动还将：(1)支持USPI与哥伦比亚卡利FC之间的梅毒免疫生物学合作研究；(2)加强国外研究所（CIDEIM）的研究能力和技术基础；(3)促进两个美国机构（UCHC和CCMC）与CIDEIM之间持续和富有成效的研究；(4)为哥伦比亚该地区提供所需的性病流行病学数据。

DESCRIPTION (provided by applicant): Venereal syphilis is a sexually transmitted disease caused by the spirochetal pathogen, Treponema pallidum. The disease remains uncontrolled, particularly in resource-scarce regions where testing, treatment and proper follow-up are not always accessible. Syphilis is characterized by the appearance of a local ulcer at the site of initial infection to an array of chronic systemic inflammatory manifestations that when left untreated, can cause severe complications and even death. The inability to culture the bacterium has hampered efforts to fully understand its pathogenesis, particularly why the spirochete is able to evade the immune system. The research proposed here is thus designed to better characterize the nature this immune response as it occurs in human syphilis. The systemic cellular innate immune response in secondary syphilis patients will be the focus of the current proposal. We hypothesize that in secondary syphilis, the presence of T. pallidum in the blood directly activates circulating monocytes and dendritic cells. To do so, in Specific Aim 1 we will first confirm that spirochetal DNA is present in blood from secondary syphilis patients using a novel Real Time Quantitative PCR method and in Specific Aim 2 we will characterize T. pallidum driven immune responses in circulating monocytes and dendritic cells by using multiparameter four color flow cytometry and `real time' PCR (RT-PCR) to quantify their pro- inflammatory cytokine gene expression signals. Complementary ex vivo studies, are structured to identify the effect of the bacterium on specific components of innate and adaptive immune cells. From these two parallel lines of research, we will obtain a more mechanistic understanding of the pathogenesis of syphilis, which can be further developed along cellular and molecular lines and ultimately facilitate development of a vaccine. In concert with the Fogarty International Center's mission to reduce health disparities amongst nations, the planned activities will also: (1) support collaborative syphilis immunobiology research between the USPI and the FC in Cali, Colombia; (2) strengthen the foreign institute's (CIDEIM), research capabilities and technical base; (3) foster sustained and productive research between two US based institutions (UCHC and CCMC) and CIDEIM; and (4) provide needed epidemiological data about venereal syphilis for that region of Colombia.