Pathoadaptive Mutations in Treponema Pallidum, the Syphilis

描述（由申请人提供）：梅毒是全球健康的一个重大问题。它是由梅毒螺旋体（Treponema pallidum subsp.苍白球（T. palidum），一种高毒性、侵袭性和难治性螺旋体。这项建议的目标是在人群范围内使用比较基因组学来确定基因突变对T。与不同组织富集相关的苍白球菌株，开发一个完善的菌株指纹方法和全基因组表达谱。比较全基因组分析将在一些T。苍白球分离株以及最近的分离株来源于具有不同临床表现和不同地理分布的患者。 具体目标如下：1.测定T.代表地理和年代多样性的苍白球分离物; 2.鉴定T.苍白球高通量从头，国家的最先进的测序方法将被用来获得一个全面的数量的基因组序列从我们收集的T。苍白球分离株我们将创建一个公开可用的数据库，其中将包括T.苍白球将进行靶向qRT-PCR分析，以确定热点对选定基因转录水平的影响。 总的来说，这些研究的完成将为我们在分子水平上对T.苍白球分离株它还将为未来的大规模研究奠定基础，在特定的遗传变异和组织/器官/系统参与之间进行全人群的关联研究，并在分子水平上更好地了解密螺旋体如何重新感染或超级感染个体。这些研究可能对临床和公共卫生问题产生深远影响。

DESCRIPTION (provided by applicant): Syphilis is a significant problem for global health. It is caused by Treponema pallidum subsp. pallidum (T. palidum), a highly virulent, invasive and intractable spirochete. The goal of this proposal is to use comparative genomics on a population-wide scale to determine the contribution of genetic mutations to the identification of T. pallidum strains associated with distinct tissue enrichments, to the development of a refined strain fingerprinting method and for genome-wide expression profiling. Comparative genome-wide analysis will be done on a number of T. pallidum isolates as well as more recent isolates originated from patients with distinct clinical presentations and diverse geographical distributions. The Specific Aims are as follows: 1. Determine the population genomic variability of T. pallidum isolates representing geographical and chronological diversity; 2. Identify repeated mutational changes (hot spot mutations) in T. pallidum. High-throughput de novo, state-of-the-art sequencing approaches will be used to obtain a comprehensive number of genome sequences from our collection of T. pallidum isolates. We will create a publicly available database that will include a genome-wide map of mutations acquired in T. pallidum. Targeted qRT-PCR analysis will be performed to determine impact of hot spots on transcript levels of selected genes. Overall, accomplishment of the proposed studies will set the basis for the advance of our understanding at the molecular level of the epidemiology of T. pallidum isolates. It will also lay the groundwork for futures studies on a large scale, population-wide association research between specific genetic variations and tissue/organ/system involvement, and for a better understanding at the molecular level of how treponemes can, for example, re-infect or super-infect individuals. These studies can have a far reaching impact on issues of clinical and public health significance.