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，并且在这段时间在西欧和中国的发生率急剧增加。除了成人严重的临床后遗症外，先天性梅毒还负责发展中国家的胎儿和新生儿发病率和死亡率很高。梅毒是一种长期性传播感染，未经治疗持续数十年。当我们的实验室发现TPRK的七个离散区域（称为V区域）的序列变化，TPRK是一种假定的表面暴露蛋白质蛋白质的蛋白质，我们假设这代表了一种抗原变异系统，导致免疫逃避并导致梅毒感染的慢性性质。梅毒仅在早期（初级和次要）阶段才通过性接触传播，那么数十年的持久性的进化优势是什么？抗原变异必须赋予细菌另一个优势。现在，我们假设T. pallidum T.抗原变异的主要优势在于感染阶段的延长：主要chancre的持续时间较长，免疫逃生以允许次生病变的发展和较长的次生病变持续时间。从早期病变中的T. pallidum的免疫清除率是通过激活的巨噬细胞对palliD的吞噬作用而发生的，因此这些病变中持续存在的生物必须能够逃避这种免疫活性以延迟病变的分辨率。这与我们较早的发现是一致的，即在体内初始免疫清除率后的病变中持续存在的treponemes对肿瘤吞噬作用具有抗性。在此续签应用中，我们建议将重点放在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区域变化在免疫逃生中的作用。具体而言，我们提出以下目的：1）定义特定抗TPRK抗体有助于清除pallidum抗体从愈合原发性病变中清除的机制； 2）确定功能性抗TPRK抗体识别的表位； 3）确定新变体是否包含次生病变中看到的treponemes； 4）研究是否由新的变体TPRK抗原诱导变异特异性抗体； 5）确定Interferon-3在新的TPRK变体开发中的作用。这些研究将阐明TPRK抗原变异有助于通过T. pallidum逃避免疫的机制，并导致梅毒感染性阶段的持续时间长。公共卫生相关性：梅毒是一种重要且常见的疾病。该赠款的应用将研究导致梅毒，毛毛虫的细菌如何逃避感染宿主的免疫反应以延长感染性周期。我们将研究一种称为TPRK的蛋白质，该蛋白被认为暴露在细菌细胞的表面上。 TPRK经历其序列的变化，这抑制了抗体结合其结合的能力，从而使细菌能够从宿主免疫中逃脱。