Extracellular Matrix Adhesins of Treponema pallidum

项目摘要/摘要 梅毒仍然是全球公共卫生的威胁，据估计，每年有1100万新感染者，而且 全球感染3600万人的负担。在过去的十年中，梅毒病例在 遍布全球各大城市，包括美国、加拿大、欧洲、澳大利亚和中国。一个 男性与男性发生性关系的人数增长尤其明显，达到了令人震惊的56% 自2011年以来观察到的增长。梅毒感染增加了感染和传播艾滋病毒的风险，以及 由母婴传播引起的先天性梅毒感染增加了88% 自2012年以来，在美国境内的子宫内。尽管梅毒可以用青霉素治疗治愈，但如果 及早诊断，全球梅毒流行表明，这种疾病不会被消除 仅通过公共卫生控制措施，将需要制定有效的战略来 防止感染这种病原体。 制定感染预防策略需要对致病菌有深入的了解 这种极为成功的病原体所使用的机制。引起梅毒的细菌--密螺旋体 梅毒，能够在感染的早期阶段在宿主内迅速传播，感染每一个 器官和组织。人们对T。 梅毒在宿主中广泛传播，并在其中获得理解 高度相关的研究领域将揭示新的候选疫苗，可以有针对性地预防 建立感染机制。 这项建议中包含的研究的长期目标是指导有效的梅毒疫苗设计。 通过增加我们对梅毒螺旋体致病机制的了解。至 为了实现这一目标，提出了以下具体目标：(1)研究T。 梅毒粘附素Tp0751与宿主内皮蛋白层粘连蛋白受体(LAMR)、口腔素和 含表皮生长因子的类纤维蛋白细胞外基质蛋白1(EFEMP1) 作为本供资期间具有Tp0751约束力的目标，以及调查T. 梅毒内皮细胞受体-血小板活化因子受体(PAFR)被认为是发挥作用的 由于与其他侵袭性病原体相似而在发病机制中的作用；(2)确定宿主内皮细胞 Tp0751和梅毒螺旋体激活的细胞信号通路促进梅毒螺旋体传播； 为了确定Tp0751/梅毒螺旋体与宿主内皮细胞结合的功能后果，在 包括整个细胞和分子水平。这些研究将增加对关键过程的理解 梅毒螺旋体的传播，有望揭示一种新的寄主信号致病策略 梅毒螺旋体使用的颠覆，使其能够跨越细胞屏障并进入内部更深的组织 主持人。

Project Summary/Abstract Syphilis remains a public health threat worldwide, with an estimated 11 million new infections per year and a global burden of 36 million infections. Within the last decade there have been outbreaks of syphilis cases in major cities around the world, including within the United States, Canada, Europe, Australia and China. A particularly sharp increase has been observed in men who have sex with men, with an alarming 56% increase observed since 2011. Syphilis infections increase the risk of acquiring and transmitting HIV, and there has been an 88% increase in congenital syphilis infections, resulting from mother to child transmission in utero, within the United States since 2012. 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 effective strategies to prevent infection with this pathogen. Development of infection prevention strategies 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. Minimal understanding exists surrounding the pathogenic mechanisms used by T. pallidum to undergo widespread dissemination throughout the host, 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 studies contained in this proposal is to guide effective syphilis vaccine design by increasing our understanding of the pathogenic mechanisms used by T. pallidum to cause disease. To accomplish this objective, the following specific aims are proposed: (1) to investigate the interaction of the T. pallidum adhesin Tp0751 with the host endothelial proteins laminin receptor (LamR), stomatin, and epidermal growth factor-containing fibulin like extracellular matrix protein 1 (EFEMP1), which were identified as Tp0751-binding targets during the current funding period, as well as to investigate the interaction of T. pallidum with the endothelial receptor platelet activating factor receptor (PAFr) which is hypothesized to play a role in pathogenesis due to parallels with other invasive pathogens; (2) to determine the host endothelial cell signaling pathways activated by Tp0751 and T. pallidum to facilitate treponemal dissemination; and (3) to determine the functional consequence of Tp0751/T. pallidum engagement with host endothelial cells, at both the whole cell and molecular levels. These studies will increase understanding of the critical process of T. pallidum dissemination and are expected to reveal a novel pathogenic strategy of host signaling subversion used by T. pallidum to enable crossing of cellular barriers and accessing of deeper tissues within the host.