Population genomics of Streptococcus pyogenes

化脓性链球菌群体基因组学

基本信息

批准号：
7570089
负责人：
Debra E BESSEN
金额：
$ 33.98万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7570089
关键词：
Address Bacteria Biology Candidate Disease Gene Chromosome Mapping Complex Genetic Trait Computer Simulation Coupled Data Disease Ecology Epidemiology Event Evolution Exhibits Experimental Models Gene Pool General Practitioners Genes Genetic Genetic Recombination Genetic Variation Genome Genomics Genotype Goals Growth Habitats Human Infection Intervention Knowledge Lead Libraries Linkage Disequilibrium Modeling Molecular Mutation Organism Orthologous Gene Outcome Measure Pathogenesis Pharyngeal structure Phenotype Point Mutation Population Prevalence Publishing Research Resolution Role Screening procedure Sensitivity and Specificity Sequence Analysis Series Shotguns Site Skin Specialist Streptococcus pyogenes Testing Tissues Virulence Virulent base comparative genomic hybridization design fitness genome sequencing in vivo in vivo Model insight microbial mutant pathogen preference success tissue tropism tool transmission process vaccine development

项目摘要

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.

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）组织向性（喉咙与皮肤）的分子基础，A 组链球菌是一种细菌病原体，在整个人类中引起高水平的疾病。世界。实现这一长期目标的第一步是描述 GAS 群体中所有遗传变异的特征，这些变异可以区分对喉咙和皮肤有强烈偏好（专家）或没有明确偏好（通才）的生物体。下一步是通过在密切模拟疾病的实验模型中测试突变体来确定哪些基因型导致组织特异性感染。最终的证据在于将一种组织特异性表型的生物体成功遗传转化为另一种组织特异性表型。初步数据表明，GAS 的组织向性是一种复杂的遗传性状，涉及多个位点。喉咙和皮肤组织特异性 GAS 感染的分子基础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）将对 GAS 群体内可能通过重组事件（插入缺失、直系同源基因置换）产生的遗传变异进行全面评估。假设除了初步研究中描述的基因型之外还发现了其他候选基因型，那么将鉴定出最有可能在组织趋向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）。用于皮肤特异性感染的新的顶级候选基因型将在皮肤专业菌株中失活，并使用体内模型测试皮肤生长的改变（目标 3）。如果没有发现新的候选基因型（目标 2），喉咙拉伤专家将转变为皮肤拉伤专家（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。这些发现将促进打破传播链的疫苗或疗法的开发，提供有关新毒力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。