Population genomics of Streptococcus pyogenes

描述（由申请人提供）：我们的长期目标是充分了解A组链球菌（GAS;化脓性链球菌）的组织嗜性（咽喉与皮肤）的分子基础，A组链球菌是一种导致全世界人类高水平疾病的细菌病原体。实现这一长期目标的第一步是表征GAS群体中的所有遗传变异，这些遗传变异区分了对喉咙和皮肤有强烈偏好的生物体（专家）或没有明确偏好的生物体（通才）。下一步是确定哪些基因型有助于组织特异性感染，通过在模拟疾病的实验模型中测试突变体。最终的证据在于一种组织特异性表型的生物体成功地遗传转化为另一种表型。初步数据表明，组织嗜性在GAS是一个复杂的遗传性状，涉及多个位点。在咽喉和皮肤的组织特异性GAS感染的分子基础上提出的问题本质上与生态学和进化生物学中的一个基本问题相同：生态位专业化的分子基础是什么，它是如何出现的？ 拟议的研究（目标1）将提供一个全面的评估遗传变异的GAS人口可能会出现通过重组事件（indels，orthopathic基因置换）。假设发现了除初步研究中描述的基因型之外的其他候选基因型，将鉴定最有可能在组织嗜性中起关键作用的基因型，并描述其获得的可能顺序（目标2）。皮肤特异性感染的新的顶级基因型候选者将在皮肤专家菌株中灭活，并使用体内模型测试皮肤生长的改变（Aim 3）。如果没有发现新的候选基因型（目标2），咽喉菌株专家将转换为皮肤菌株专家（目标3）。拟议的研究将采用一种综合方法，结合微生物基因组学，流行病学，进化生物学和实验发病机制的工具。这些发现将促进疫苗或疗法的开发，打破传播链，提供关于新的毒性克隆出现的分子变化的见解，并开始解决进化生物学中的一个基本问题。

DESCRIPTION (provided by applicant): Our long-term objective is to fully understand the molecular basis underlying tissue tropisms (throat versus skin) in group A streptococci (GAS; Streptococcus pyogenes), a bacterial pathogen causing high levels of disease in humans throughout the world. A first step towards this long-term goal is to characterize all genetic variation within the GAS population that differentiates organisms having strong preferences for the throat versus skin (specialists), or no clear cut preference (generalists). A next step is to determine which genotypes contribute to tissue-specific infection, by testing mutants in an experimental model that closely mimics disease. Final proof lies in the successful genetic conversion an organism of one tissue-specific phenotype to the other phenotype. Preliminary data suggest that tissue tropism in GAS is a complex genetic trait, involving multiple loci. The question raised on the molecular basis for tissue-specific GAS infections at the throat and skin is, in essence, the same as a fundamental question in ecology and evolutionary biology: What is the molecular basis for niche specialization, and how does it emerge? The proposed research (Aim 1) will provide a comprehensive assessment of the genetic variation within the GAS population that likely arises via recombination events (indels, orthologous gene displacements). Assuming that additional genotype candidates are uncovered, beyond those described in preliminary studies, the genotypes that are most likely to have a critical role in tissue tropism will be identified and the likely order of their acquisition will be delineated (Aim 2). New top-ranking genotype candidates for skin-specific infection will be inactivated in a skin specialist strain, and tested for altered growth at the skin using an in vivo model (Aim 3). If no new genotype candidates are uncovered (Aim 2), a throat strain specialist will be converted to a skin strain specialist (Aim 3). The proposed study will employ an integrated approach that combines tools of microbial genomics, epidemiology, evolutionary biology, and experimental pathogenesis. The findings will promote development of vaccines or therapies that break the chain of transmission, provide insights on the molecular changes surrounding the emergence of new virulent clones, and begin to address a fundamental question in evolutionary biology.