Extracellular Matrix Adhesins of Treponema pallidum

梅毒螺旋体细胞外基质粘附素

• 批准号: 7630384
• 负责人: CAROLINE E CAMERON
• 金额: $ 24万
• 依托单位: UNIVERSITY OF VICTORIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7630384
• 关键词: Bacteria; Bacterial Adhesins; Bacterial Infections; Binding; Biological Models; Carbohydrates; Cardiovascular system; Cattle; Cells; Childhood; Chronic; Cities; Congenital Syphilis; Data; Dermatitis; Developed Countries; Developing Countries; Development; Disease Outbreaks; Eastern Europe; Europe; Exhibits; Extracellular Matrix; Funding; Genes; Genetic; Globus Pallidus; Goals; Grant; HIV; Health; Homologous Gene; Homologous Protein; Human; Immunization; In Vitro; Infection; Invaded; Investigation; Knowledge; Laminin; Lead; Mediating; Molecular; Nature; Neoplasm Metastasis; North America; Open Reading Frames; Operon; Order Spirochaetales; Organism; Pathogenesis; Penetration; Periodontal Diseases; Play; Polysaccharides; Prevention; Process; Proteins; Public Health; Reagent; Reporting; Risk; Role; Route; Screening procedure; Synteny; Syphilis; Techniques; Time; Tissues; Treponema denticola; Treponema pallidum; Treponema pallidum adhesin; Treponema phagedenis; Treponemal Infections; Work; combat; defined contribution; digital; field study; in vivo; insight; men who have sex with men; novel; oral spirochetes; pathogen; protein function; protein protein interaction; research study; transmission process

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.

描述（由申请人提供）：梅毒，由螺旋体细菌梅毒螺旋体亚种引起。苍白球是一种慢性细菌感染，仍然是全世界的公共卫生问题。虽然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，最近在欧洲和北美的城市中，据报在男男性行为者中爆发了疫情。此外，传染性梅毒通过另外两种途径直接影响人类健康;先天性梅毒仍然是全球重要的儿科健康问题，梅毒感染导致传播和获得人类免疫缺陷病毒（HIV）的风险增加。T.苍白球与宿主细胞和组织的相互作用在感染过程中至关重要，但对该病原体用于启动和建立感染的致病机制知之甚少。梅毒螺旋体是一种高度侵袭性的病原体;附着于宿主细胞后，该生物体侵入组织屏障并进入循环系统，导致细菌广泛传播。传播病原体的一个关键特征是附着于细胞外基质（ECM）组分层粘连蛋白的能力。本文重点研究了T.在前一个资助期内鉴定的苍白球层粘连蛋白结合粘附素Tp 0751，并专门研究其对密螺旋体感染过程的贡献。在这个提议中，层粘连蛋白分子上介导Tp 0751附着的碳水化合物残基将通过筛选碳水化合物微阵列来鉴定。这些信息将允许详细了解的TP 0751-层粘连蛋白的相互作用，并确定这种相互作用的发病机制的意义。该提案还将关注位于Tp 0751、Tp 0750上游的共转录开放阅读框架。推测Tp 0750与Tp 0751协同作用，促进T.苍白球，这一拟议的作用将在此进行调查。在两个相关的密螺旋体中发现了这些蛋白质的同源物，并且提出了利用可培养的密螺旋体作为模型系统来研究这些蛋白质在密螺旋体发病机制中的作用的实验。此外，这些蛋白质对细菌转移的贡献将通过体外和体内传播抑制实验来确定。本建议中所包含的研究的长期目标是扩大我们对T。苍白球发病机制提供了一个详细的研究，在传播这种细菌的关键分子。加强对T.梅毒感染过程将允许开发新的试剂来对抗梅毒感染。在这一研究领域取得的进展将对公共卫生产生重大影响，既直接通过预防性传播和先天传播的梅毒感染，也间接通过减少艾滋病毒的感染和传播。