Systemic Innate Immune Responses in Secondary Syphilis

描述（由申请人提供）：性病梅毒是一种由螺旋体病原体梅毒螺旋体引起的性传播疾病。这种疾病仍然得不到控制，特别是在资源匮乏的地区，那里并不总是能够得到检测、治疗和适当的后续行动。梅毒的特征是在初始感染部位出现局部溃疡，并出现一系列慢性全身性炎症表现，如果不进行治疗，可能导致严重的并发症甚至死亡。无法培养这种细菌阻碍了充分了解其发病机制的努力，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在人类梅毒中发生的性质。二期梅毒患者的系统性细胞天然免疫反应将是目前建议的重点。我们推测，在二期梅毒中，T。血液中的苍白球直接激活循环单核细胞和树突细胞。为此，在具体目标1中，我们将首先使用新的真实的时间定量PCR方法确认螺旋体DNA存在于来自二期梅毒患者的血液中，并且在具体目标2中，我们将表征T。通过使用多参数四色流式细胞术和“真实的时间”PCR（RT-PCR）定量它们的促炎细胞因子基因表达信号，在循环单核细胞和树突细胞中检测苍白球驱动的免疫应答。互补的离体研究被构造成鉴定细菌对先天性和适应性免疫细胞的特定组分的影响。从这两条平行的研究路线中，我们将获得对梅毒发病机制的更机理的理解，这可以进一步沿着细胞和分子路线发展，并最终促进疫苗的开发。为配合福格蒂国际中心缩小各国之间健康差距的使命，计划开展的活动还将：（1）支持USPI和哥伦比亚卡利FC之间的梅毒免疫生物学合作研究;（2）加强外国研究所（CIDEIM）的研究能力和技术基础;（3）促进两个美国机构（UCHC和CCMC）和CIDEIM之间的持续和富有成效的研究;（4）提供哥伦比亚该地区所需的性病梅毒流行病学数据。

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.