Antigenic Variation of TprK in Treponema pallidum

梅毒螺旋体TprK抗原变异

• 批准号: 7741287
• 负责人: Sheila A. Lukehart
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741287
• 关键词: Adult; Amino Acids; Antibodies; Antigenic Variation; Antigens; Applications Grants; Bacteria; Binding; Biological Assay; Borrelia burgdorferi; Cells; Chicago; China; Chronic; Clinical; Congenital Syphilis; Developed Countries; Developing Countries; Development; Disease; Environment; Epitopes; Gene Conversion; Genome; Globus Pallidus; Grant; Healed; Human; Immobilization; Immune; Immune Sera; Immune response; Immunity; Immunosuppression; Incidence; Infection; Interferons; Laboratories; Lesion; Link; Macrophage Activation; Mediating; Minor; Modeling; Molecular; Nature; Order Spirochaetales; Organism; Oryctolagus cuniculus; Pathogenesis; Phagocytosis; Plague; Primary Lesion; Production; Proteins; Recombinants; Resistance; Resolution; Role; Secondary Lesion; Sexually Transmitted Diseases; Specificity; Staging; Surface; Syphilis; Syphilitic chancre; System; T-Lymphocyte; Testing; Time; Treponema pallidum; United States; Variant; Western Europe; fetal; healing; immune clearance; immunogenic; in vivo; inhibitor/antagonist; killings; macrophage; mortality; neonatal morbidity; pathogen; prevent; public health relevance; response; skin lesion; success

DESCRIPTION (provided by applicant): The incidence of infectious syphilis has doubled in the United States since 2000, and has increased dramatically in Western Europe and in China during that time. In addition to serious clinical sequelae in adults, congenital syphilis is responsible for a high proportion of fetal and neonatal morbidity and mortality in developing countries. Syphilis is a chronic sexually transmitted infection which, untreated, lasts for many decades. When our laboratory discovered sequence variation in seven discrete regions (termed V regions) of TprK, a putative surface- exposed protein of Treponema pallidum, we hypothesized that this represents an antigenic variation system, leading to immune evasion and contributing to the chronic nature of syphilis infection. Syphilis is transmissible by sexual contact only during the early (primary and secondary) stages, however, so what is the evolutionary advantage of decades-long persistence? Antigenic variation must impart another advantage to the bacterium. We now hypothesize that the major advantage of TprK antigenic variation by T. pallidum lies in the prolongation of the infectious stages: longer duration of the primary chancre, immune escape to permit development of secondary lesions, and longer duration of secondary lesions. Immune clearance of T. pallidum from early lesions occurs via phagocytosis of opsonized T. pallidum by activated macrophages, so organisms persisting in these lesions must be able to evade this immune activity to delay lesion resolution. This is consistent with our earlier finding that treponemes persisting in lesions following initial immune clearance in vivo are resistant to opsonophagocytosis. In this renewal application, we propose to focus on the early stages of syphilis infection in the rabbit model and to define, at the molecular and functional level, the role of TprK V region variation in immune escape. Specifically, we propose the following aims: 1) Define the mechanism(s) by which specific anti-TprK antibodies contribute to the clearance of T. pallidum from healing primary lesions; 2) Identify the epitopes recognized by functional anti- TprK antibodies; 3) Determine whether new variants comprise the treponemes seen in secondary lesions; 4) Investigate whether variant-specific antibodies are induced by new variant TprK antigens; and 5) Determine the role of interferon-3 in development of new TprK variants. These studies will elucidate the mechanisms by which TprK antigenic variation contributes to immune evasion by T. pallidum and leads to long duration of the infectious stages of syphilis. PUBLIC HEALTH RELEVANCE: Syphilis is an important and common disease. This grant application will study how the bacterium that causes syphilis, Treponema pallidum, evades the immune response of the infected host to prolong the period of infectivity. We will study a protein called TprK that is thought to be exposed on the surface of the bacterial cell. TprK undergoes changes in its sequence which inhibits the ability of antibodies to bind it, thus enabling the bacterium to escape from host immunity.

描述（由申请人提供）：自2000年以来，传染性梅毒的发病率在美国翻了一番，在西欧和中国也急剧增加。除了严重的成人临床后遗症外，先天性梅毒在发展中国家胎儿和新生儿发病率和死亡率中所占比例很高。梅毒是一种慢性性传播感染，未经治疗可持续数十年。当我们的实验室发现梅毒螺旋体表面暴露蛋白TprK的七个离散区域（称为V区）的序列变异时，我们假设这代表了抗原变异系统，导致免疫逃避并导致梅毒感染的慢性性质。梅毒仅在早期（原发性和继发性）阶段通过性接触传播，然而，那么数十年的持续存在的进化优势是什么？抗原性变异一定给细菌带来了另一个优势。我们现在假设，T. pallidum引起的TprK抗原变异的主要优势在于延长感染阶段：原发性下疳持续时间更长，免疫逃逸使继发病变得以发展，继发病变持续时间更长。早期病变的免疫清除是通过活化的巨噬细胞吞噬活化的苍白球，因此在这些病变中持续存在的生物体必须能够逃避这种免疫活性以延迟病变消退。这与我们早期的发现一致，即体内初始免疫清除后，在病变中持续存在的螺旋体对调性噬噬有抵抗力。在这项更新申请中，我们建议将重点放在兔模型梅毒感染的早期阶段，并在分子和功能水平上确定TprK V区变异在免疫逃逸中的作用。具体而言，我们提出以下目标：1)确定特异性抗tprk抗体有助于清除T. pallidum愈合原发病变的机制；2)鉴定功能性抗TprK抗体识别的表位；3)确定继发性病变中是否有新的梅毒螺旋体变异；4)研究变异TprK抗原是否诱导变异特异性抗体；5)确定干扰素-3在新的TprK变异发展中的作用。这些研究将阐明TprK抗原变异导致梅毒t免疫逃避的机制，并导致梅毒感染期持续时间长。公共卫生相关性：梅毒是一种重要的常见病。这项拨款申请将研究导致梅毒的梅毒螺旋体（Treponema pallidum）细菌如何避开受感染宿主的免疫反应，从而延长感染期。我们将研究一种叫做TprK的蛋白质，这种蛋白质被认为暴露在细菌细胞表面。TprK的序列发生变化，从而抑制抗体结合它的能力，从而使细菌能够逃脱宿主的免疫。