Predicting species-wide virulence for a bacterial pathogen with a large pan-genome

预测具有大型泛基因组的细菌病原体的物种范围毒力

• 批准号: 9199847
• 负责人: Tim van Opijnen
• 金额: $ 23.48万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-05 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199847
• 关键词: Affect; Bacteria; Cessation of life; Characteristics; Clinical; Cluster Analysis; Data; Development; Disease; Epithelial Cells; Etiology; Gene Pool; Genes; Genetic; Genome; Genomics; Genotype; Goals; Growth; Infection; Invaded; Knowledge; Lead; Libraries; Life; Lung; Massive Parallel Sequencing; Measures; Methods; Mus; Mutagenesis; Nasopharynx; Organism; Pathway interactions; Pattern; Phenotype; Play; Pneumococcal Infections; Pneumonia; Process; Role; Sampling; Streptococcus pneumoniae; Techniques; Untranslated RNA; Vacuum; Variant; Virulence; adaptive learning; antimicrobial; design; experimental study; fitness; genetic element; genome-wide; genomic variation; high throughput analysis; in vivo; killings; member; mouse model; neglect; novel; pan-genome; pathogen; pathogenic bacteria; public health relevance; species difference; success; tool

 DESCRIPTION (provided by applicant): Genomic variation between bacterial strains from the same species can be so large that no two genomes may contain the same content. This has lead to a distinction between a species' core-genome (the pool of genes shared by all members of a species) and pan-genome (a species' global gene repertoire). Consequently, although strains belong to the same species, differences in the presence and absence of genomic content means that they may not function in the same manner, potentially affecting all sorts of phenotypes including bacterial virulence. A growing body of evidence suggests that the genetic background effect is actually a broad phenomenon that can be observed in different domains of life. However, due to difficulties associated with performing both genome-wide as well as species-wide experiments, comprehensive studies have so far been neglected. With the introduction of the genome- wide tool transposon sequencing (Tn-seq, a method we developed), it has now become feasible to untangle the influence of the genetic-background on a genome-wide scale and a species-wide level for a bacterial pathogen. Here we focus on the bacterium Streptococcus pneumoniae a common occupant of the nasopharynx, with a pan-genome 3-fold larger than the core-genome, and a major etiology of illness worldwide causing tens of millions of episodes of invasive pneumococcal disease and ~1.5 million deaths each year. We hypothesize that a diverse set of genes, pathways and small non-coding RNAs (ncRNAs), are involved in virulence and due to differences in genetic-background these components and the roles they play are only partially conserved across strains. We propose to determine in detail the virulence potential for 50 S. pneumoniae strains, covering 92% of the pan-genome, thereby unraveling the genomic-patterns that are most important for host-colonization and disease induction. This will enable us to predict: 1) the virulence-level of a genotype, and 2) a genotype's likelihood to evolve a higher virulence-level. Thereby this proposal fits into the major long-term goal of the lab, which is to understand how bacteria induce disease on a species-wide level in order to apply this knowledge to enable predictions on a strain's potential virulence, and design species-wide antimicrobial strategies.

 描述（由申请人提供）：来自相同物种的细菌菌株之间的基因组变异可能非常大，以至于没有两个基因组可能包含相同的内容。这导致了物种核心基因组（物种所有成员共享的基因库）和泛基因组（物种的全球基因库）之间的区别。因此，尽管菌株属于同一物种，但基因组内容存在和不存在的差异意味着它们可能不以相同的方式发挥作用，可能影响所有种类的表型，包括细菌毒力。越来越多的证据表明，遗传背景效应实际上是一种广泛的现象，可以在生命的不同领域中观察到。然而，由于与进行全基因组以及物种范围的实验相关的困难，迄今为止，全面的研究一直被忽视。随着全基因组工具转座子测序（Tn-seq，我们开发的一种方法）的引入，解开细菌病原体在全基因组范围和物种范围水平上的遗传背景的影响现在已经变得可行。在这里，我们专注于细菌肺炎链球菌鼻咽部的常见居民，具有比核心基因组大3倍的泛基因组，并且是全球范围内导致数千万次侵袭性肺炎球菌疾病发作和每年约150万例死亡的主要病因。我们假设一组不同的基因、途径和小的非编码RNA（ncRNA）参与毒力，并且由于遗传背景的差异，这些组分及其所起的作用在菌株中仅部分保守。我们建议详细确定50 S的毒力潜力。pneumoniae菌株，覆盖了92%的泛基因组，从而揭示了对宿主定殖和疾病诱导最重要的基因组模式。这将使我们能够预测：1）基因型的遗传水平，以及2）基因型进化更高遗传水平的可能性。因此，这一建议符合主要的 该实验室的长期目标是了解细菌如何在物种范围内诱导疾病，以便应用这些知识来预测菌株的潜在毒力， 设计物种范围的抗菌策略。

项目成果

Bacterial Factors Required for Transmission of Streptococcus pneumoniae in Mammalian Hosts.

• DOI: 10.1016/j.chom.2019.04.012
• 发表时间: 2019-06
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Hannah M. Rowe;E. Karlsson;H. Echlin;Ti‐Cheng Chang;Lei Wang;T. van Opijnen;S. Pounds;S. Schultz‐Cherry;J. Rosch