Treponema pallidum:Pathogenesis-associated molecules

描述（由申请人提供）：数百万人已经并将继续感染致病性密螺旋体，包括三种梅毒螺旋体亚种和卡拉密螺旋体。由此产生的疾病——性病梅毒、雅司病、bejel和pint——都是慢性的、潜在的使人衰弱和毁容的疾病。全球每年约有1100万新发梅毒病例：自2000年以来，传染性梅毒在美国增加了一倍，在欧洲重新出现，在中国增加了10倍。估计至少有250万例非性病螺旋体感染。虽然在感染期间对同源苍白球绦虫菌株产生免疫，但这种免疫可能对其他菌株无效，对其他亚种也没有交叉保护作用。因此，即使经过有效治疗，重复感染也很常见，从而使感染在人群中保持不变。因此，细微的抗原差异是致病性密螺旋体保护性免疫的关键。白僵菌的致病亚种是非常密切相关的，比较遗传学研究表明，亚种之间的遗传差异主要存在于tpr基因家族的12个成员中，其编码的蛋白质是抗原的，其中一些可能位于细菌的外膜，准备与宿主和免疫系统相互作用。该应用主要集中在TprC和TprD上，它们被预测为表面暴露，具有高度免疫原性，并且在亚种和菌株中含有不同的氨基酸区域。TprC和D的表面暴露得到了计算机算法、3D蛋白预测以及最重要的功能上的调理吞噬试验的支持。我们假设抗原差异，定位于TprC和D的表面暴露环，在对苍白t亚种的免疫中具有功能意义，并且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)确定白螺旋体多个亚种和菌株中TprC和Tpr D的潜在表面暴露区域；2)明确TprC和TprD中感染诱导和免疫诱导的T细胞和B细胞表位；3)利用同源和异源苍白球绦虫菌株作为功能检测的靶点，确定TprC和D的不同区域在功能性免疫中的作用；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。这一知识对于了解人群中螺旋体感染的持续传播和确定有效疫苗的成分至关重要。

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.