Extracellular Matix Adhesins of Treponema pallidum

描述（由申请人提供）：梅毒仍然是全球范围内的公共卫生威胁，估计每年有1200万新感染，全球负担为2500万感染。在过去十年中，世界各大城市的梅毒疫情有所增加，中国和加拿大的梅毒感染增加了10倍，美国的梅毒感染增加了一倍。梅毒感染增加了获得和传播艾滋病毒的风险，近年来，在美国，由于母婴在子宫内传播，先天性梅毒感染增加了23%。 States.虽然梅毒是可以治愈的青霉素治疗，如果早期诊断，世界范围内的梅毒流行表明，消除这种疾病不会发生单独通过公共卫生控制措施，而是需要开发一种有效的梅毒疫苗。梅毒疫苗的开发需要深入了解这种非常成功的病原体的致病机制。引起梅毒的细菌，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。T.苍白球在整个宿主中进行广泛传播的可能性尚不清楚，并且在这一高度相关的研究领域内获得理解将揭示可以靶向预防感染建立的新疫苗候选物。该研究项目的长期目标是阐明促进T.梅毒螺旋体宿主成分和广泛的密螺旋体传播，特别是，以确定两个T。苍白球蛋白酶，pallilysin和Tp 0750，在这一重要的致病过程。为了实现这一目标，提出了以下具体目标：（1）阐明pallilysin和Tp 0750的宿主成分附着和蛋白水解的机制：（2）确定这两种蛋白酶利用宿主纤溶过程的能力，该过程是正常宿主成分降解和周转所必需的;（3）利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T.（4）直接确定这两种蛋白酶在T.苍白球这些研究将加深对T.梅毒传播，并将揭示合适的疫苗候选人预防梅毒感染。

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.