Treponema pallidum:Pathogenesis-associated molecules

梅毒螺旋体：发病机制相关分子

• 批准号: 8675784
• 负责人: Sheila A. Lukehart
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675784
• 关键词: 3-Dimensional; Accounting; Address; Affect; Africa South of the Sahara; Amino Acids; Antibiotics; Antibodies; Antigens; Area; Asia; B-Lymphocyte Epitopes; Bacteria; Biological Assay; Biology; China; Chronic; Communities; Computational algorithm; Congenital Syphilis; Data; Disease; Disease Outbreaks; Dose; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitope Mapping; Europe; Family; Funding; Gene Family; Genes; Genetic; HIV; Heterogeneity; Immune Sera; Immune response; Immune system; Immunity; Immunization; Immunology; Individual; Infection; Institutes; Knowledge; Laboratories; Lesion; Location; Macrolide-resistance; Membrane; Membrane Proteins; Molecular; Oral; Organism; Pathogenesis; Persons; Pinta; Population; Protein Region; Proteins; Recombinant Proteins; Recombinants; Recording of previous events; Research; Role; Sexually Transmitted Diseases; Structural Models; Structure; Surface; Surgeon; Syphilis; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Treponema; Treponema pallidum; Treponemal Infections; United States; Vaccines; Western Europe; Work; Yaws; attenuation; comparative; cross immunity; effective therapy; immunogenic; interest; member; prevent; stillbirth; three-dimensional modeling; transmission process; vaccine development

DESCRIPTION (provided by applicant): Millions of people have been, and continue to be, infected by pathogenic Treponema, including the three Treponema pallidum subspecies and Treponema carateum. The resulting diseases-venereal syphilis, yaws, bejel, and pinta-are all chronic, potentially debilitating and disfiguring diseases. Globally, there are ~11 million new cases of syphilis annually: infectious syphilis has doubled in the United States since 2000, has re- emerged in Europe, and has increased 10-fold in China. At least 2.5 million cases of nonvenereal treponemal infections are estimated. While immunity to the homologous T. pallidum strain develops during infection, that immunity may be ineffective for other strains and is not cross-protective to other subspecies. Consequently, repeated infection is common, even after effective treatment, thus maintaining the infection within populations. Subtle antigenic differences, then, are key to protective immunity in the pathogenic Treponema. The pathogenic subspecies of T. pallidum are very closely related and comparative genetic studies have revealed that much of the genetic difference among the subspecies resides in the 12-member tpr gene family, whose encoded proteins are antigenic and several of which may be located in the outer membrane of the bacterium, poised for interaction with the host and the immune system. This application focuses on TprC and TprD which are predicted to be surface exposed, are highly immunogenic, and which contain amino acid regions that are distinct among subspecies and strains. Surface exposure of TprC and D is supported by computer algorithms, 3D protein predictions, and, most importantly, functionally by opsonophagocytosis assays. We hypothesize that antigenic differences, localized to surface exposed loops of TprC and D, have functional significance in immunity to the T. pallidum subspecies and relate to the lack of cross-immunity among subspecies and strains. We propose the following aims: 1) Identify potential surface-exposed regions of TprC and Tpr D in multiple subspecies and strains of T. pallidum; 2) Define infection-induced and immunization-induced T and B cell epitopes in TprC and TprD; 3) Determine the role of the distinct regions of TprC and D in functional immunity, using homologous and heterologous T. pallidum strains as the targets of the functional assays; 4) Determine whether there is a role for conserved regions of TprC and TprD in immunity. Identification of antigens that contribute to cross-immunity is a means of defining the protective antigens of the pathogenic treponemes. This knowledge is critical to understanding the continued transmission of treponemal infections within populations and to determining the components of an effective vaccine.

描述（由申请人提供）：数以百万计的人已经并且继续被致病性毛虫感染，包括三种treponema pallidum pallidum subspecies和treponema carateum。由此产生的疾病 - 敏感性梅毒，偏航，贝杰尔和Pinta-都是慢性的，有可能使人衰弱和毁容疾病。在全球范围内，每年有1100万例新的梅毒病例：自2000年以来，感染性梅毒在美国增加了一倍，在欧洲出现，在中国增加了10倍。估计至少有250万例非veneal毛发性三次人性感染。尽管在感染期间对同源型颗粒菌株的免疫力发展，但免疫力可能对其他菌株无效，并且对其他亚种没有交叉保护。因此，即使经过有效的治疗，重复感染也很常见，从而维持了种群中的感染。因此，细微的抗原差异是致病性曲纳马保护性免疫的关键。 T. pallidum的致病性亚种密切相关，比较遗传研究表明，亚种之间的许多遗传差异都存在于12个成员的TPR基因家族中，TPR基因家族的编码蛋白是抗原蛋白是抗原性的，其中几种可能位于细菌的外膜，以与宿主的相互作用，并与宿主相互作用。该应用集中在TPRC和TPRD上，这些TPRC和TPRD被认为是表面暴露的，具有高度免疫原性，并且包含在亚种和菌株之间与众不同的氨基酸区域。 TPRC和D的表面暴露由计算机算法，3D蛋白预测以及最重要的是，在功能上由肿瘤细胞增多症测定法支持。我们假设将抗原差定位在TPRC和D的表面暴露环中，对pallidum t. t. t. subspecies的免疫具有功能意义，并且与亚种和菌株之间缺乏跨免疫性有关。 我们提出以下目的：1）在多个t. pallidum的多个亚种和菌株中确定TPRC和TPR D的潜在表面暴露区域； 2）定义感染诱导的和免疫诱导的TPRC和TPRD中的T和B细胞表位； 3）使用同源和异源T. pallidum菌株作为功能分析的靶标，确定TPRC和D不同区域在功能免疫中的作用； 4）确定TPRC和TPRD保守区域在免疫中是否有作用。 鉴定有助于跨免疫力的抗原是定义致病性毛treponemes保护性抗原的一种手段。这些知识对于理解人群中的链球菌感染的持续传播以及确定有效疫苗的成分至关重要。