Treponema pallidum:Pathogenesis-associated molecules

描述(申请人提供)：数以百万计的人已经并将继续感染致病性梅毒螺旋体，包括三个梅毒螺旋体亚种和卡特密螺旋体。由此产生的疾病--性病梅毒、雅司病、梅毒和皮疹--都是慢性的、可能使人衰弱和毁容的疾病。全球每年新增梅毒病例约1100万例：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250万非性病梅毒螺旋体感染病例。虽然对同源梅毒螺旋体的免疫力是在感染过程中形成的，但这种免疫力对其他菌株可能无效，对其他亚种也没有交叉保护作用。因此，反复感染是常见的，即使在有效的治疗之后也是如此，因此在人群中保持感染。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。梅毒螺旋体的致病亚种之间关系密切，比较遗传学研究表明，亚种间的大部分遗传差异存在于12个成员的TPR基因家族中，其编码的蛋白质是抗原性的，其中几个可能位于细菌的外膜，准备与宿主和免疫系统相互作用。这项应用主要针对TprC和TprD，它们预计会暴露在表面，具有高度的免疫原性，并且含有不同亚种和菌株之间不同的氨基酸区域。TprC和D的表面暴露得到了计算机算法和3D蛋白质预测的支持，最重要的是，功能上得到了吞噬细胞分析的支持。我们推测，抗原差异定位于TprC和D的表面暴露环，对梅毒螺旋体亚种的免疫具有功能意义，并与亚种和菌株之间缺乏交叉免疫有关。我们提出的目标如下：1)在多个梅毒螺旋体亚种和菌株中确定潜在的TprC和TprD表面暴露区域；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)以同源和异源梅毒螺旋体菌株为靶标，确定TprC和TprD不同区域在功能免疫中的作用；4)确定TprC和TprD保守区是否在免疫中起作用。识别有助于交叉免疫的抗原是确定致病性梅毒螺旋体保护性抗原的一种手段。这一知识对于了解梅毒螺旋体感染在人群中的持续传播以及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.