Treponema pallidum: Pathogenesis-associated molecules

描述（由申请方提供）：致病螺旋体的亚种，苍白密螺旋体，是梅毒、雅司病和贝热尔病的病原体。T. carateum引起人类感染，pinta.梅毒在发达国家引起流行病，在发展中国家是地方病;估计每年有1 200万人感染。雅司病、贝杰尔病和平他病发生在发展中国家的偏远地区，像梅毒一样，这些疾病会导致慢性残疾。T. paraluiscuniculi与T.梅毒，引起兔子的性病梅毒，但对人类没有传染性。这些致病性密螺旋体的感染和侵袭性的临床表现在种和亚种之间有显著差异。此外，针对致病性密螺旋体的感染诱导的免疫力在物种或亚种间是弱的或不存在的，但在致病性密螺旋体的亚种内更强。基于这些数据，我们推断独特的基因序列定义了不同的临床疾病。类似地，亚种间相同的抗原不太可能具有完全保护性，而种或亚种特有的那些抗原最有可能对完全保护至关重要。tpr基因家族被认为与密螺旋体感染的发病机制有关，我们已经在几个tpr基因中鉴定出亚种特异性序列。本更新申请提出：1）鉴定三个亚种的菌株之间tpr基因序列及其编码蛋白的差异; pallidum和相关的兔病原体T. paraluiscuniculi，使用聚焦基因测序。2)检测三个亚种中tpr基因的转录水平。pallidum和T. paraluiscuniculi，作为亚种/种属、组织位置和感染后时间的函数。3)鉴定选定的Tpr抗原的T和B细胞表位，重点是那些在致病性密螺旋体的菌株、亚种或种之间序列不同的蛋白质。4)确定亚种或种特异性Tpr序列和基因表达在疫苗诱导免疫中的相对贡献。这些研究将导致鉴定对密螺旋体感染的发病机制和保护性免疫重要的特定分子。LAV语言的相关性：被称为密螺旋体的细菌每年在全球数百万人中引起几种不同的、严重的和持续的感染。这些研究将测试某些基因，称为tpr基因，是否可以用来区分一种感染和另一种感染，以及对这些细菌的免疫反应是否可以保护免受感染。

DESCRIPTION (provided by applicant): Subspecies of the pathogenic spirochete, Treponema pallidum, are the agents of syphilis, yaws, and bejel. T. carateum causes the human infection, pinta. Syphilis causes epidemics in the developed world and is endemic in the developing world; an estimated 12 million people are infected every year. Yaws, bejel, and pinta occur in isolated areas of the developing world and, like syphilis, these diseases can cause chronic disability. T. paraluiscuniculi is closely related to T. pallidum and causes venereal syphilis in rabbits, but is not infectious for humans. The clinical manifestations of infection and invasiveness of these pathogenic treponemes are significantly different among species and subspecies. Moreover, infection-induced immunity against the pathogenic treponemes is weak or non-existent across species or subspecies, but is more robust within a subspecies of pathogenic treponeme. Based on these data, we have reasoned that unique genetic sequences define the different clinical diseases. Similarly, antigens that are identical among the subspecies are unlikely to be completely protective, while those antigens that are unique to species or subspecies are most likely to be critical for complete protection. The tpr gene family is thought to be relevant to pathogenesis of treponemal infection, and we have already identified subspecies-specific sequences in several tpr genes. This renewal application proposes to 1) Identify differences in the sequences of tpr genes and their encoded proteins among strains of the three subspecies of T. pallidum and in the related rabbit pathogen T. paraluiscuniculi, using focused gene sequencing. 2) Examine the levels of transcription of the tpr genes in the three subspecies of T. pallidum and in T. paraluiscuniculi, as a function of subspecies/species, tissue location, and time after infection. 3) Identify the T and B cell epitopes of selected Tpr antigens, focusing on those proteins that differ in sequence among strains, subspecies, or species of pathogenic treponemes. 4) Determine the relative contribution of subspecies- or species-specific Tpr sequences and gene expression in vaccine-induced immunity. These studies will lead to the identification of specific molecules that are important to the pathogenesis of treponemal infections and protective immunity. Relevance in lav language: Bacteria known as Treponema cause several different, serious and persistent infections in millions of people globally each year. These studies will test whether certain genes, called tpr genes, can be used to tell one infection from another and whether the immune response to these bacteria can protect against infection.