Mechanisms of Immune Evasion and Recognition in Human Syphilis

人类梅毒的免疫逃避和识别机制

• 批准号: 8411525
• 负责人: Adriana Raquel Cruz
• 金额: $ 4.83万
• 依托单位: CENTRO INTERNACIONAL (CIDEIM)
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411525
• 关键词: Address; Antibodies; Antibody Formation; Antibody Repertoire; Appearance; Bacteria; Binding; Blood; Characteristics; Chronic; Clinical; Colombia; Data; Dendritic Cells; Dermal; Developing Countries; Diagnosis; Disease; Epidemiology; Exhibits; Freeze Fracturing; Glycolipids; Goals; Gram-Negative Bacteria; Health; Health Professional; Host Defense; Human; Immune; Immune Cell Activation; Immune response; Immunobiology; Immunologic Factors; Immunologic Receptors; Immunologics; Individual; Infection; Inflammation; Integral Membrane Protein; Invaded; Latent Syphilis; Lesion; Lipids; Lipopolysaccharides; Mediating; Membrane; Membrane Proteins; Microscopy; Mission; Modeling; N-terminal; Natural Killer Cells; Nature; Order Spirochaetales; Organ; Organism; Pathogenesis; Patients; Play; Population; Production; Public Health; Research; Research Activity; Resolution; Role; Sexually Transmitted Diseases; Signs and Symptoms; Skin; Staging; Surface; Syphilis; Syphilitic chancre; T-Lymphocyte; Time; Tissues; Toll-like receptors; Training and Education; Treponema pallidum; United States; Western Europe; Wit; World Health Organization; authority; base; body system; cell mediated immune response; cytokine; health disparity; innovation; international center; macrophage; pathogen; periplasm; polypeptide; public health relevance; translational approach; uptake

DESCRIPTION (provided by applicant): Syphilis, a multi-stage sexually transmitted disease caused by the spirochete Treponema pallidum (Tp), continues to be a major worldwide public health problem. The World Health Organization (WHO) estimates that approximately 10.6 million new syphilis cases occur yearly throughout the globe. The clinical manifestations of syphilis reflect the propensity of Tp to disseminate systemically and induce a chronic inflammation which occurs in stages, being secondary syphilis (SS) the focus of this proposal. Despite the robust nature of the adaptive and humoral immune responses during SS, including the emergence of high titers of opsonic antibodies, it takes weeks to months for host defenses to gain control of the invading pathogen. How the bacterium is able to evade human host defenses, while at the same time evoking vigorous cellular and humoral immune responses, is the principal scientific objective of the current proposal. A careful analysis of Tp¿s unique ultrastructural characteristics, which contains very few outer membrane proteins (OMPs), provides potential explanations for the paradoxical nature of SS. Inefficient antibody binding to the sparse spirochetal OMP antigenic targets is thought to allow a large proportion of spirochetes to shun antibody binding and opsonophagocytosis; a mechanism which we have shown is an essential requirement for Tp driven innate immune cell activation. The new finding that circulating natural killer (NK) cells reveal immunophenotypic alterations (emergence of a CD56negativeCD16high NK-cell subset), which exhibits both poor cytolytic activity and impaired cytokine production suggests that additional immunologic factors play a role in the duality of the immune response to Tp. We now propose a new syphilis immune-pathogenesis model, where antibodies to Tp¿s rare OMPs are only capable of binding a sub-population of spirochetes, thus allowing immune escape of organisms and at the same time recognition and bacterial clearance of different tissues. Over time, the host's expanding repertoire of antibodies against these rare OMPs broadens and intensifies, leading to more efficient opsonophagocytosis, bacterial clearance and lesion resolution. To accomplish our goals and examine mechanistic aspects of the proposed model, we have formulated the following Specific Aims. In Aim 1: we will further characterize spirochete burdens, spirochete diversity and the antibody responses in the blood of secondary syphilis patients; and in aim 2: we will study the role of the dermal macrophage as a driver of both inflammation and spirochetal clearance in secondary syphilis patient's dermal lesions. And in aim 3, w will further characterize NK cells in blood of SS patients. In concert wit 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 LMIC PI and the US collaborators (2) strengthen CIDEIM¿s research capabilities and technical base; (3) continue providing needed epidemiological data about venereal syphilis for that region of Colombia.

描述（由申请人提供）：梅毒是一种由梅毒螺旋体 (Tp) 引起的多阶段性传播疾病，世界卫生组织 (WHO) 估计约有 1060 万新梅毒患者仍然是全球主要的公共卫生问题。全球每年都会发生梅毒病例，其临床表现反映了 Tp 系统性传播并诱发分阶段发生的继发性慢性炎症的倾向。梅毒（SS）是该提案的重点，尽管 SS 期间适应性和体液免疫反应具有强大的性质，包括高滴度调理性抗体的出现，但宿主防御需要数周至数月才能控制入侵的病原体。该细菌如何能够逃避人类宿主的防御，同时引发强烈的细胞和体液免疫反应，是当前提案的主要科学目标。其独特的超微结构特征含有很少的外膜蛋白（OMP），这为 SS 的矛盾性质提供了可能的解释，即抗体与稀疏螺旋体 OMP 抗原靶点的低效结合被认为是导致大部分螺旋体回避抗体结合的原因。我们已经证明，调理吞噬作用是 Tp 驱动的先天免疫细胞激活的基本要求，这一新发现表明循环自然杀伤 (NK) 细胞揭示了免疫表型改变。 （CD56阴性CD16high NK细胞亚群的出现）表现出较差的细胞溶解活性和受损的细胞因子产生，这表明额外的免疫因素在对Tp的免疫反应的双重性中发挥作用，我们现在提出了一种新的梅毒免疫发病机制。其中 Tp 抗体罕见的 OMP 只能结合螺旋体的一个亚群，从而允许生物体进行免疫逃逸，同时识别和清除不同组织的细菌。随着时间的推移，宿主针对这些罕见的 OMP 的抗体库不断扩大和加强。 ，从而实现更有效的调理吞噬作用、细菌清除和病变消解，为了实现我们的目标并检查所提出模型的机制方面，我们在目标 1 中制定了以下具体目标：我们将进一步表征二期梅毒患者血液中的螺旋体负荷、螺旋体多样性和抗体反应；目标 2：我们将研究真皮巨噬细胞作为二期梅毒患者皮肤病变中炎症和螺旋体清除的驱动因素的作用；在目标 3 中，我们将进一步表征 SS 患者血液中的 NK 细胞，以配合福格蒂国际中心减少国家间健康差异的使命。活动还将：(1) 支持 LMIC PI 和美国合作者之间的梅毒免疫生物学合作研究 (2) 加强 CIDEIM¿ (3) 继续提供哥伦比亚该地区所需的性梅毒流行病学数据。