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，美国传染性梅毒的发病率增加了一倍，而在此期间西欧和中国的发病率也急剧增加。除了成人严重的临床后遗症外，先天性梅毒也是发展中国家胎儿和新生儿发病率和死亡率很高的原因。梅毒是一种慢性性传播感染，如果不加以治疗，会持续数十年。当我们的实验室发现 TprK（一种推定的梅毒螺旋体表面暴露蛋白）的七个离散区域（称为 V 区）的序列变异时，我们假设这代表了一个抗原变异系统，导致免疫逃避并导致梅毒的慢性性质感染。然而，梅毒只能在早期（一期和二期）阶段通过性接触传播，那么持续数十年的进化优势是什么？抗原变异必然赋予细菌另一个优势。我们现在假设梅毒螺旋体 TprK 抗原变异的主要优点在于延长感染阶段：原发性下疳的持续时间更长，免疫逃逸允许继发性病变的发展，以及继发性病变的持续时间更长。早期病变中梅毒螺旋体的免疫清除是通过活化的巨噬细胞吞噬调理后的梅毒螺旋体而发生的，因此持续存在于这些病变中的生物体必须能够逃避这种免疫活动以延迟病变消退。这与我们之前的发现一致，即体内初始免疫清除后病变中持续存在的密螺旋体对调理吞噬作用具有抵抗力。在此更新申请中，我们建议重点关注兔模型中梅毒感染的早期阶段，并在分子和功能水平上定义 TprK V 区变异在免疫逃逸中的作用。具体来说，我们提出以下目标： 1) 明确特异性抗 TprK 抗体有助于清除梅毒螺旋体从治愈原发病变中的机制； 2) 鉴定功能性抗TprK抗体识别的表位； 3) 确定新的变异体是否包含继发性病变中所见的密螺旋体； 4) 研究新变异TprK抗原是否诱导变异特异性抗体； 5) 确定干扰素 3 在新 TprK 变体开发中的作用。这些研究将阐明 TprK 抗原变异导致梅毒螺旋体免疫逃避并导致梅毒感染阶段持续时间较长的机制。公共卫生相关性：梅毒是一种重要且常见的疾病。该拨款申请将研究引起梅毒的细菌梅毒螺旋体如何逃避感染宿主的免疫反应以延长感染期。我们将研究一种名为 TprK 的蛋白质，该蛋白质被认为暴露在细菌细胞表面。 TprK 的序列发生变化，抑制抗体与其结合的能力，从而使细菌逃避宿主免疫。