Treponema pallidum:Pathogenesis-associated molecules

描述（由申请人提供）：数百万人已经并将继续受到致病性密螺旋体的感染，包括三种梅毒密螺旋体亚种和Carateum密螺旋体。由此产生的疾病性病梅毒、雅司病、贝杰尔病和品他病都是慢性的、潜在的使人衰弱和毁容的疾病。在全球范围内，每年约有1100万例梅毒新发病例：自2000年以来，传染性梅毒在美国翻了一番，在欧洲重新出现，在中国增加了10倍。估计至少有250万例非性病密螺旋体感染病例。而对同源T.在感染过程中，梅毒菌株的发展，免疫力可能是无效的其他菌株，并没有交叉保护其他亚种。因此，反复感染是常见的，即使在有效的治疗后，从而保持人口内的感染。因此，细微的抗原差异是致病密螺旋体保护性免疫的关键。 病原亚种T.梅毒螺旋体和梅毒螺旋体的亲缘关系非常密切，比较遗传学研究显示，这两个亚种之间的遗传差异主要在于由12个成员组成的tpr基因家族，其编码的蛋白质具有抗原性，其中几种可能位于细菌的外膜上，随时准备与宿主和免疫系统相互作用。本申请集中于TprC和TprD，其被预测为表面暴露的，具有高度免疫原性，并且其含有在亚种和菌株之间不同的氨基酸区域。TprC和D的表面暴露得到计算机算法、3D蛋白预测以及最重要的是调理吞噬测定的功能支持。我们假设，抗原差异，定位于表面暴露的环的TprC和D，有功能的意义，免疫T。梅毒螺旋体亚种之间的差异与亚种和菌株之间缺乏交叉免疫有关。 我们提出了以下目标：1）确定TprC和TprD在多个亚种和菌株中的潜在表面暴露区域;苍白球; 2）确定TprC和TprD中感染诱导和免疫诱导的T和B细胞表位; 3）使用同源和异源T. 4）确定TprC和TprD的保守区域是否在免疫中起作用。 鉴定有助于交叉免疫的抗原是确定致病性密螺旋体的保护性抗原的一种手段。这一知识对于了解密螺旋体感染在人群中的持续传播和确定有效疫苗的成分至关重要。 公共卫生相关性：梅毒影响全球约2500万人，尽管治疗有效，但过去十年中美国、欧洲和亚洲的梅毒感染人数有所上升。这项研究将有助于确定对引起梅毒的细菌的保护性免疫反应的目标，并将有助于我们了解感染是如何在社区中维持的。

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. PUBLIC HEALTH RELEVANCE: Syphilis affects approximately 25 million globally and, despite effective treatment, the number of syphilis infections has risen in the United States, Europe and Asia during the past decade. This research will help to determine the targets of the protective immune response to the bacterium causing syphilis, and will help us to understand how the infection is maintained in a community.