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翻了一番，在此期间，西欧和中国的发病率急剧上升。除了成人严重的临床后遗症外，先天性梅毒在发展中国家的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，如不治疗，可持续数十年。当我们的实验室发现TprK（梅毒螺旋体的一种假定的表面暴露蛋白）的七个离散区域（称为V区域）中的序列变异时，我们假设这代表抗原变异系统，导致免疫逃避并促成梅毒感染的慢性性质。然而，梅毒只有在早期（初级和次级）阶段才能通过性接触传播，那么几十年的持续存在有什么进化优势呢？抗原变异必然会给细菌带来另一个优势。我们现在假设T.苍白病的原因在于感染期的延长：原发性下疳持续时间较长，免疫逃逸导致继发性病变的发展，以及继发性病变持续时间较长。T.来自早期病变的苍白球通过吞噬调理的T.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，即在体内初始免疫清除后，在病变中持续存在的密螺旋体对调理吞作用具有抗性。在这个更新的应用程序中，我们建议集中在早期阶段的梅毒感染的兔模型和定义，在分子和功能水平上，TprK V区的变化在免疫逃逸的作用。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T清除的机制。本发明的目的在于：2）鉴定由功能性抗TprK抗体识别的表位; 3）确定新的变体是否包含在继发性病变中看到的密螺旋体; 4）研究变体特异性抗体是否由新的变体TprK抗原诱导;和5）确定干扰素-3在新的TprK变体的发展中的作用。这些研究将阐明TprK抗原变异导致T.梅毒的症状是什么？公共卫生相关性：梅毒是一种重要和常见的疾病。这项拨款申请将研究导致梅毒的细菌，梅毒螺旋体，如何逃避受感染宿主的免疫反应，以延长传染期。我们将研究一种被称为TprK的蛋白质，它被认为暴露在细菌细胞的表面。TprK的序列发生变化，抑制了抗体结合它的能力，从而使细菌能够逃避宿主免疫。