Extracellular Matix Adhesins of Treponema pallidum

描述(由申请人提供)：梅毒仍然是世界范围内的公共卫生威胁，估计每年有1200万新感染病例，全球有2500万感染病例。在过去的十年里，世界主要城市的梅毒疫情有所增加，中国和加拿大的梅毒感染人数增加了10倍，美国的梅毒感染人数翻了一番。梅毒感染增加了感染和传播艾滋病毒的风险，近年来，在美国，由母婴传播引起的先天性梅毒感染增加了23% 各州。尽管如果及早诊断梅毒是可以用青霉素治疗治愈的，但全世界的梅毒流行表明，仅靠公共卫生控制措施无法消除这种疾病，相反，需要开发有效的梅毒疫苗。梅毒疫苗的开发需要深入了解这种高度成功的病原体所使用的致病机制。导致梅毒的细菌梅毒螺旋体能够在感染的早期阶段在宿主内迅速传播，感染每个器官和组织。梅毒螺旋体在宿主中广泛传播的致病机制尚不清楚，在这一高度相关的研究领域内获得理解将揭示新的候选疫苗，可以有针对性地防止感染的建立。该研究项目的长期目标是阐明促进梅毒螺旋体附着于宿主成分和广泛传播梅毒螺旋体的机制，特别是确定两种梅毒螺旋体蛋白水解酶pallilysin和Tp0750在这一重要致病过程中的作用。为了实现这一目标，提出了以下具体目标：(1)阐明苍白球蛋白和Tp0750的宿主组分附着和蛋白分解的机制；(2)确定这两种酶利用宿主纤溶过程的能力，这是正常宿主组分降解和周转所必需的；(3)使用敏感的蛋白质组学方法和“模型”密螺旋体来确定这两种蛋白酶在梅毒螺旋体中的位置；以及(4)直接确定这两种酶在梅毒螺旋体传播中的作用。这些研究将增加对梅毒传播关键过程的了解，并将揭示预防梅毒感染的合适疫苗候选。

DESCRIPTION (provided by applicant): Syphilis remains a public health threat worldwide, with an estimated 12 million new infections per year and a global burden of 25 million infections. Within the last decade there has been an increase in syphilis outbreaks in major cities around the world, with a 10-fold increase in syphilis infections documented for China and Canada and a doubling of syphilis infections in the United States. Syphilis infections increase the risk of acquiring and transmitting HIV, and there has been a 23% increase in congenital syphilis infections, resulting from mother to child transmission in utero, in recent years within the United States. Although syphilis is curable with penicillin treatment if diagnosed early, the worldwide syphilis prevalence shows that elimination of this disease will not occur through public health control measures alone, and instead will require development of an effective syphilis vaccine. Development of a syphilis vaccine requires an in depth knowledge of the pathogenic mechanisms used by this highly successful pathogen. The bacterium that causes syphilis, Treponema pallidum, is able to disseminate rapidly within the host during the early stages of infection to infect every organ and tissue. The pathogenic mechanisms used by T. pallidum to undergo widespread dissemination throughout the host are not known, and gaining understanding within this highly relevant area of study will reveal novel vaccine candidates that can be targeted to prevent establishment of infection. The long-term objective of the research project is to elucidate the mechanisms that facilitate attachment of T. pallidum to host components and widespread treponemal dissemination and, specifically, to determine the role of two T. pallidum proteases, pallilysin and Tp0750, in this important pathogenic process. To accomplish this objective, the following specific aims are proposed: (1) to elucidate the mechanism of host component attachment and proteolysis for pallilysin and Tp0750; (2) to determine the ability of these two proteases to exploit the host fibrinolytic process that is essential for normal host component degradation and turnover; (3) to use sensitive proteomic methodologies and a "model" treponeme to determine the location of these two proteases within T. pallidum; and (4) to directly determine the role these two proteases play in dissemination of T. pallidum. These studies will increase understanding of the critical process of T. pallidum dissemination and will reveal suitable vaccine candidates for prevention of syphilis infection.