Extracellular Matrix Adhesins of Treponema pallidum

描述(申请人提供)：梅毒，由螺旋体细菌梅毒螺旋体亚种引起。梅毒是一种慢性细菌感染，仍然是世界范围内的公共卫生问题。尽管大多数病例发生在发展中国家，但在过去几年中，东欧的病例数量迅速增加，据报道，最近在欧洲和北美各地的城市中爆发了男男性行为者疫情。此外，传染性梅毒通过另外两种途径直接影响人类健康；先天性梅毒仍然是世界范围内一个重要的儿科健康问题，梅毒感染导致传播和感染人类免疫缺陷病毒(艾滋病毒)的风险增加。梅毒螺旋体与宿主细胞和组织的相互作用在感染过程中是至关重要的，但人们对这种病原体启动和建立感染的致病机制知之甚少。梅毒螺旋体是一种侵袭性很强的病原体，与宿主细胞附着后，侵入组织屏障，进入循环系统，导致细菌广泛传播。传播病原体的一个关键特征是附着在细胞外基质(ECM)组分层粘连蛋白的能力。这项建议侧重于在前一个资助期间发现的梅毒螺旋体结合层粘连蛋白粘附素Tp0751，并具体研究其在梅毒螺旋体感染过程中的作用。在这项提案中，层粘连蛋白分子上介导Tp0751结合的碳水化合物残基将通过碳水化合物微阵列的筛选来鉴定。这些信息将有助于详细了解Tp0751-层粘连蛋白的相互作用，并确定这种相互作用对发病机制的意义。该提案还将侧重于位于Tp0751、Tp0750上游的共转录开放阅读框架。假定Tp0750与Tp0751协同工作，以促进梅毒螺旋体的入侵和传播，本文将研究这一拟议的作用。在两个相关的密螺旋体中发现了这些蛋白的同源物，并建议利用可培养的密螺旋体作为模型系统来研究这些蛋白在密螺旋体发病中的作用。此外，这些蛋白质对细菌转移的贡献将通过体外和体内扩散抑制实验来确定。这项建议中包含的研究的长期目标是通过详细研究参与梅毒螺旋体传播的关键分子来扩大我们对梅毒螺旋体发病机制的了解。加强对梅毒螺旋体感染过程的了解将有助于开发新的试剂来对抗梅毒感染。这一研究领域取得的进展将对公共卫生产生重大影响，直接通过防止性传播和先天传播的梅毒感染，间接通过同时减少艾滋病毒的获取和传播。

DESCRIPTION (provided by applicant): Syphilis, caused by the spirochete bacterium Treponema pallidum subsp. pallidum, is a chronic bacterial infection that remains a public health concern worldwide. Although the majority of the cases occur in developing nations, within the last several years a rapid increase in the number of cases occurring in eastern Europe has been observed, and recent outbreaks have been reported among men who have sex with men in cities across Europe and North America. Further, infectious syphilis directly impacts human health through two additional routes; congenital syphilis continues to be an important pediatric health concern worldwide, and syphilis infection leads to an increased risk of transmission and acquisition of the human immunodeficiency virus (HIV). Interaction of T. pallidum with host cells and tissues is crucial to the infection process, yet little is known about the pathogenic mechanisms used by this pathogen to initiate and establish infection. Treponema pallidum is a highly invasive pathogen; following attachment to host cells, the organism invades the tissue barrier and enters the circulatory system, resulting in widespread bacterial dissemination. One feature crucial to disseminating pathogens is the capacity to attach to the extracellular matrix (ECM) component laminin. This proposal focuses upon the T. pallidum laminin-binding adhesin Tp0751 identified during the previous funding period, and specifically investigates its contribution to the treponemal infection process. In this proposal, the carbohydrate residues on the laminin molecule mediating attachment of Tp0751 will be identified via screening of carbohydrate microarrays. This information will allow for a detailed understanding of the Tp0751-laminin interaction and for determination of the significance of this interaction to pathogenesis. The proposal will also focus upon the co-transcribed open reading frame located upstream of Tp0751, Tp0750. Tp0750 is hypothesized to work in concert with Tp0751 to facilitate invasion and dissemination of T. pallidum, and this proposed role will be investigated herein. Homologs of these proteins are found in two related treponemes, and experiments are proposed to utilize a culturable treponeme as a model system to study the role of these proteins in treponemal pathogenesis. Further, the contribution of these proteins to bacterial metastasis will be determined via in vitro and in vivo dissemination inhibition experiments. The long-term objective of the studies contained in this proposal is to expand our knowledge of T. pallidum pathogenesis by providing a detailed study of the key molecules involved in dissemination of this bacterium. An enhanced understanding of the T. pallidum infection process will allow for the development of novel reagents to combat syphilis infection. Advances made in this field of study will significantly impact public health, both directly through prevention of sexually- and congenitally-transmitted syphilis infections, and indirectly through a concurrent reduction in the acquisition and transmission of HIV.