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（由适用提供）：梅毒，这是由螺旋体treponema Pallidum（TP）引起的多阶段性传播疾病，它仍然是全球主要的公共卫生问题。世界卫生组织（WHO）估计，全球每年发生了大约1060万新的梅毒病例。梅毒的临床表现反映了TP有望全身传播并诱发慢性炎症，尽管SS期间适应性和人类免疫调查的性质鲁棒性，包括OPSONIC抗体的高滴度的出现，但数周至数月的数周才能获得宿主防御能力来控制入侵的病原体。细菌如何能够逃避人类的宿主防御措施，同时唤起剧烈的细胞和人类免疫复杂，这是当前建议的主要科学目标。对TP的独特超微结构特征的仔细分析，其中包含很少的外膜蛋白（OMP），为SS的矛盾性提供了潜在的解释。人们认为与稀疏的螺旋体OMP抗原靶标结合效率低下的抗体被认为允许很大一部分螺旋体避免抗体结合和肠吞噬作用。我们已经显示的一种机制是TP驱动先天免疫细胞激活的重要要求。循环自然杀手（NK）细胞的新发现揭示了免疫表型的改变（CD56NegativeCD16High NK-Cell子群的出现），既表现出较差的细胞溶解活性，又表现出细胞因子的不良生产，表明其他免疫因子在免疫方案对TP的双重性中起作用。现在，我们提出了一种新的梅毒免疫物理改变，其中TP稀有OMP的抗体仅能够结合螺旋体的亚群，从而可以使生物体的免疫逃脱以及同时识别和自由基清除不同组织。随着时间的流逝，宿主对这些罕见OMP的抗体扩展的曲目扩大和增强，从而导致更有效的调查性胞毒性，根治性清除和病变分辨率。为了实现我们的目标并检查了所提出的模型的机械方面，我们已经制定了以下特定目标。在AIM 1中：我们将进一步表征螺旋体伯良，螺旋体多样性以及继发性梅毒患者血液中的抗体反应；在AIM 2中：我们将研究皮肤巨噬细胞作为继发性梅毒患者皮肤病变中炎症和脊柱清除率的驱动力的作用。在AIM 3中，W将进一步表征SS患者血液中的NK细胞。在Fogarty International Center旨在减少国家之间的健康分配的使命中，计划中的活动还将：（1）支持LMIC PI与美国合作者之间的合作梅毒免疫生物学研究（2）增强Cideim？的研究能力和技术基础； （3）继续提供有关哥伦比亚该地区的有关性梅毒所需的流行病学数据。