Pathoadaptive evolution of Salmonella

描述（由申请人提供）：拟定的研究旨在了解单核苷酸多态性、插入/缺失或其他突变变化如何促成S。肠道菌血清型，适应于温血宿主（包括家养动物），并在人类中引起伤寒或非伤寒感染。我们的目的是检查每一个基因共享的特定致病谱系的S。肠道作为一个潜在的目标，积极选择突变的病理适应性。为此，我们将采用适应冷血和温血宿主的沙门氏菌分离株的比较遗传分析，以及后者中引起全身性、非全身性和无症状感染的沙门氏菌分离株。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重新测序。将分析遗传多态性以获得正选择的足迹。使用额外的分离株，我们将研究突变变化与特定栖息地或感染类型引起的菌株之间的关联。在一些遗传位点的突变的病理适应性将进行实验研究，在体外和体内模型。因此，我们计划获得（i）S的映射。肠道沙门氏菌基因的突变，有助于宿主的适应性和毒力的目标。肠;（ii）这些基因中可能以病理适应性方式影响基因/蛋白质功能的天然突变列表，以及（iii）沙门氏菌毒力进化的全面系统发育史和动力学模型。叙事。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遗传变化，这些沙门氏菌感染温血动物并导致人类伤寒或非伤寒疾病。

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.