Antigenic Variation of TprK in Treponema pallidum

描述(申请人提供)：自2000年以来，美国的传染性梅毒发病率增加了一倍，在此期间，西欧和中国的发病率大幅上升。除了成人的严重临床后遗症外，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占很高比例。梅毒是一种慢性性传播感染，如果不治疗，会持续数十年。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，我们推测这是一个抗原变异系统，导致免疫逃避，并导致梅毒感染的慢性性质。然而，梅毒只能通过性接触在早期(初级和次级)传播，那么持续数十年的进化优势是什么？抗原性变异一定会给细菌带来另一个优势。我们现在假设，梅毒螺旋体TprK抗原变异的主要优势在于延长了感染阶段：原发下巴持续时间更长，免疫逃逸允许发生继发损害，继发损害持续时间更长。梅毒螺旋体从早期皮损中的免疫清除是通过激活的巨噬细胞吞噬调理的梅毒螺旋体而发生的，因此坚持在这些皮损中的生物必须能够逃避这种免疫活性，以推迟皮损的消退。这与我们早期的发现是一致的，即在体内最初的免疫清除后，在皮损中持续存在的梅毒螺旋体对吞噬细胞具有抵抗力。在这一新的应用中，我们建议将重点放在梅毒感染的兔模型的早期阶段，并在分子和功能水平上确定TprK V区变异在免疫逃避中的作用。具体地说，我们提出以下目标：1)确定特定的抗TprK抗体有助于清除梅毒螺旋体从愈合的原发皮损中的机制；2)确定功能性抗TprK抗体识别的表位；3)确定新的变种是否包括继发性皮损中看到的密螺旋体；4)调查新的变种TprK抗原是否诱导变种特异性抗体；以及5)确定干扰素-3在新的TprK变种的发展中的作用。这些研究将阐明TprK抗原变异有助于梅毒螺旋体逃避免疫并导致梅毒感染阶段持续时间延长的机制。公共卫生相关性：梅毒是一种重要而常见的疾病。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，以延长感染期。我们将研究一种名为TprK的蛋白质，它被认为暴露在细菌细胞的表面。TprK的序列发生了变化，从而抑制了抗体与其结合的能力，从而使细菌能够逃避宿主的免疫。

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.