Population genomics of Streptococcus pyogenes

化脓性链球菌群体基因组学

基本信息

批准号：
7369749
负责人：
Debra E BESSEN
金额：
$ 34.71万
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 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369749
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 Medical Surveillance Modeling Molecular Mutation Organism Orthologous Gene Outcome Measure Pathogenesis Pharyngeal structure Phenotype Point Mutation Polymerase Chain Reaction Population Prevalence Publishing Range 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

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 Medical Surveillance Modeling Molecular Mutation Organism Orthologous Gene Outcome Measure Pathogenesis Pharyngeal structure Phenotype Point Mutation Polymerase Chain Reaction Population Prevalence Publishing Range 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

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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链球菌（气体； pyogenes链球菌）的分子基础组织对流（喉咙与皮肤），这是一种细菌病原体，导致全世界人类的高水平疾病。朝着这一长期目标迈出的第一步是表征气体种群中的所有遗传变异，该遗传变异区分了对喉咙与皮肤相对于皮肤（专家）或没有明确切割偏好（通才）具有强烈偏好的生物。下一步是通过测试密切模仿疾病的实验模型中测试突变体，确定哪些基因型有助于组织特异性感染。最终证明在于成功的遗传转化率一个组织特异性表型的生物体与另一种表型的生物体。初步数据表明，气体中的组织端主是一个复杂的遗传特征，涉及多个基因座。在喉咙和皮肤上组织特异性气体感染的分子基础上提出的问题本质上与生态和进化生物学中的基本问题相同：利基专业的分子基础是什么？它如何出现？拟议的研究（AIM 1）将对气体种群内的遗传变异进行全面评估，这可能是通过重组事件（Indels，直系同源基因位移）而产生的。假设发现了其他基因型候选者，除了初步研究中描述的基因型外，最有可能在组织端主中具有关键作用的基因型将被鉴定出来，并且可能会划定其获取的顺序（AIM 2）。新的顶级基因型候选针对皮肤特异性感染的候选者将在皮肤专家菌株中灭活，并使用体内模型测试了皮肤上生长的改变（AIM 3）。如果没有发现新的基因型候选物（AIM 2），则喉咙菌株专家将转换为皮肤菌株专家（AIM 3）。拟议的研究将采用一种综合方法，该方法结合了微生物基因组学，流行病学，进化生物学和实验性发病机理的工具。这些发现将促进破坏传播链的疫苗或疗法的开发，提供有关围绕新的有毒克隆出现的分子变化的见解，并开始解决进化生物学中的基本问题。