Systemic Innate Immune Responses in Secondary Syphilis

二期梅毒的全身先天免疫反应

• 批准号: 7547764
• 负责人: Juan C Salazar
• 金额: $ 5.08万
• 依托单位: CONNECTICUT CHILDREN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547764
• 关键词: Animal Model; Antibodies; Antigenic Specificity; Antigens; Appearance; Bacteria; Biological Models; Blood; Cells; Cessation of life; Chronic; Clinical; Colombia; Color; Communicable Diseases; Contracts; Cytokine Gene; DNA; Data; Dendritic Cells; Disease; Elements; Epidemiology; Flow Cytometry; Fostering; Gene Expression; Globus Pallidus; HIV; Homing; Human; Immune; Immune response; Immune system; Immunobiology; Immunologic Memory; Immunologics; In Vitro; Infection; Inflammatory; Inflammatory Response; Institutes; Institution; Investigation; Left; Lesion; Lipoproteins; Mediating; Methods; Mission; Molecular; Natural Immunity; Nature; Order Spirochaetales; Organ; Pathogenesis; Patients; Property; Research; Resources; Risk Factors; Sexually Transmitted Diseases; Signal Transduction; Site; Skin; Structure; Syphilis; T-Lymphocyte; Testing; Time; Time Study; Tissues; Treponema pallidum; Ulcer; World Health Organization; base; design; follow-up; health disparity; in vivo Model; insight; international center; lymph nodes; monocyte; novel; parent grant; pathogen; peripheral blood; response; transmission process; vaccine development

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.

描述（由申请人提供）： 性病梅毒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，这些地区并不总是能够进行检测、治疗和适当的随访。梅毒的特点是在最初感染部位出现局部溃疡，并出现一系列慢性全身炎症表现，如果不及时治疗，可能会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，特别是螺旋体为何能够逃避免疫系统。因此，本文提出的研究旨在更好地表征人类梅毒中发生的这种免疫反应的性质。二期梅毒患者的全身细胞先天免疫反应将是当前提案的重点。我们假设，在二期梅毒中，血液中梅毒螺旋体的存在直接激活循环单核细胞和树突状细胞。为此，在具体目标 1 中，我们将首先使用新型实时定量 PCR 方法确认二期梅毒患者的血液中存在螺旋体 DNA，在具体目标 2 中，我们将使用多参数四色流式细胞术和“实时”PCR (RT-PCR) 来量化其促炎细胞因子，从而表征循环单核细胞和树突状细胞中梅毒螺旋体驱动的免疫反应。 基因表达信号。补充性离体研究旨在确定细菌对先天性和适应性免疫细胞特定成分的影响。从这两条平行的研究中，我们将对梅毒的发病机制获得更机械的理解，这可以沿着细胞和分子路线进一步发展，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 之间持续且富有成效的研究； (4) 提供哥伦比亚该地区所需的性梅毒流行病学数据。