Treponema pallidum:Pathogenesis-associated molecules

描述(申请人提供)：致病螺旋体的亚种梅毒螺旋体，梅毒，雅司病和贝耶尔。卡氏毛滴虫会引起人类感染，品塔。梅毒在发达国家造成流行，在发展中国家流行；估计每年有1200万人感染梅毒。雅司病、贝耶尔病和皮塔病发生在发展中国家与世隔绝的地区，像梅毒一样，这些疾病可以导致慢性残疾。副钩端螺旋体与梅毒螺旋体关系密切，可引起兔的性病梅毒，但对人类不具传染性。这些病原性密螺旋体的感染和侵袭性的临床表现在物种和亚种之间存在显著差异。此外，感染诱导的对病原性密螺旋体的免疫在种或亚种之间很弱或不存在，但在致病性密螺旋体的一个亚种内更强。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。同样，亚种之间相同的抗原不太可能具有完全保护作用，而那些物种或亚种独有的抗原很可能是完全保护的关键。TPR基因家族被认为与梅毒螺旋体感染的发病机制有关，我们已经在几个TPR基因中确定了亚种特异性序列。这一新的应用提出：1)利用聚焦基因测序，鉴定梅毒螺旋体三个亚种的菌株及其编码蛋白在TPR基因序列和相关兔病原体Tpr基因序列上的差异。2)检测TPR基因在梅毒螺旋体三个亚种和副钩端螺旋体中的转录水平，作为亚种/种、组织位置和感染后时间的函数。3)确定选定的Tpr抗原的T和B细胞表位，重点研究致病性梅毒螺旋体不同菌株、亚种或物种之间序列差异的蛋白质。4)确定亚种或物种特异性Tpr序列和基因表达在疫苗诱导免疫中的相对贡献。这些研究将导致识别对梅毒螺旋体感染和保护性免疫的发病机制至关重要的特定分子。与LAV语言相关：每年，全球数百万人中，被称为密螺旋体的细菌会导致几种不同的、严重的和持续的感染。这些研究将测试被称为TPR基因的某些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能够防止感染。

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.