Pathoadaptive evolution of Salmonella

描述(由申请人提供)：拟议的研究旨在了解单核苷酸多态、插入/缺失或其他突变变化如何有助于适应温血宿主(包括家养动物)的肠杆菌血清型的出现，并导致人类感染伤寒或非伤寒。我们的目的是检查肠球菌特定致病谱系共有的每一个基因，作为病理适应性突变的阳性选择的潜在目标。为此，我们将对适应冷血和温血宿主的沙门氏菌分离株进行比较遗传分析，并对后者中那些引起系统性、非系统性和无症状感染的沙门氏菌进行比较分析。我们预计将使用30-40个完全测序的基因组进行分析，大约相同或更多数量的菌株对将通过突变平铺微阵列进行重新测序。遗传多态将被分析，以寻找积极选择的足迹。使用更多的菌株，我们将调查突变变化与来自特定栖息地或感染类型的菌株的关联。我们将使用体外和体内模型，通过实验来检验某些基因座突变的病理适应性。因此，我们计划获得(I)针对导致肠杆菌宿主适应和毒力的突变的肠杆菌基因图谱；(Ii)这些基因中可能以致病适应方式影响基因/蛋白质功能的自然发生突变的列表；以及(Iii)沙门氏菌毒力进化的全面系统发育历史和动力学模型。叙事性。我们建议剖析导致人类感染的沙门氏菌菌株毒力进化的分子基础。我们将确定导致沙门氏菌出现的基因变化，这些沙门氏菌正在感染温血动物，并在人类中引起伤寒或非伤寒疾病。

DESCRIPTION (provided by applicant): The proposed studies are directed at understanding how single nucleotide polymorphisms, insertion/deletions, or other mutational changes contribute to the emergence of S. enterica serovars adapted to warm-blooded hosts (including domesticated animals) and which cause typhoid or non-typhoid infections in humans. Our aim is to examine every gene shared by specific pathogenic lineages of S. enterica as being a potential target for positive selection for mutations of a pathoadaptive nature. To do this, we will employ comparative genetic analyses of Salmonella isolates adapted to cold- and warm-blooded hosts and, among the latter, those causing systemic, non-systemic and asymptomatic infections. We expect to use 30-40 fully sequenced genomes for the analysis and about the same or a larger number of strain pairs will be resequenced by mutation tiling microarrays. Genetic polymorphisms will be analyzed for a footprint of positive selection. Using additional isolates, we will investigate association of the mutational changes with strains from specific habitats or types of infection caused. The pathoadaptive nature of mutations in some of the genetic loci will be examined experimentally, using both in vitro and in vivo models. As a result, we plan to obtain (i) a map of S. enterica genes targeted for mutations that contribute to the host adaptation and virulence of S. enterica; (ii) a list of naturally-occurring mutations in these genes that likely affect the gene/protein function in a pathoadaptive manner, and (iii) a comprehensive phylogenetic history and dynamics model of the evolution of virulence in Salmonella. Narrative. We propose to dissect molecular basis of evolution of virulence of Salmonella strains that cause human infections. We will determine genetic changes that contribute to emergence of Salmonella that are infecting warm-blooded animals and cause typhoid or non-typhoid disease in humans.