Molecular Mechanisms of Staphylococcus Epidermidis Strain Diversity

表皮葡萄球菌菌株多样性的分子机制

• 批准号: 10412521
• 负责人: Julia S Oh
• 金额: $ 3.6万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412521
• 关键词: Admixture; Bacteria; CRISPR interference; Environment; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genome; Genomic approach; Goals; Growth; Health; Homeostasis; Human; Individual; Infection; Infectious Skin Diseases; Investigation; Knowledge; Life Style; Medical Device; Molecular; Phenotype; Phylogenetic Analysis; Population; Public Health; Role; Sepsis; Skin; Staphylococcus epidermidis; Virulence; disorder risk; gene function; genetic strain; immunoregulation; insight; knock-down; medical implant; member; microbial; microbial community; mucosal microbiota; pan-genome; pathogen; prevent; skin microbiota; tool

PROJECT SUMMARY / ABSTRACT Staphylococcus epidermidis is a ubiquitous member of the human skin and mucosal microbiota. Functionally, it is a key contributor to human health via immune modulation and microbial community homeostasis. Yet the ‘commensal’ S. epidermidis is also an important pathogen and disease risk reservoir—it is the most frequent cause of medical device and bloodstream infections. Multiple phylogenetically diverse subspecies, or strains, of S. epidermidis can co-inhabit the skin with genomes of variable gene content. The overwhelming majority of these genes have unknown function. We hypothesize that this variable gene content, or accessory genome, interacts with core genes to enable strains to uniquely respond to and thrive in different environments, and that mixing of these genetically diverse strains is necessary to maintain a healthy homeostasis in the skin. To investigate the function of these genes and to understand how genetic diversity at the strain level contributes to population-level phenotype, we will functionally profile a set of phylogenetically diverse strains isolated from healthy individuals and individuals with bloodstream infections. We will create CRISPRi tools for gene knockdown in S. epidermidis to systematically identify strain-specific and core genes that underlie the ability to colonize and compete in the skin and infections. Aim 1 develops the CRISPRi genetic toolkit to created pooled S. epidermidis knockdown pools. Phenotypic profiling these pools will greatly expand our knowledge of important commensal strategies employed by a common microbial partner, and how genetic heterogeneity may impact the commensal to infectious transition. Aim 2 investigates the role of strain admixture in this transition. This combination of genomic approaches and mechanistic studies will provide the first investigation into the function of the S. epidermidis pangenome. Annotating inter-strain genetic diversity will reveal new insights into the functional consequence of strain diversity: how strains can successfully transition between commensal and virulence lifestyles, and how multiple strains can co-exist in an ecological network.

项目总结/摘要 表皮葡萄球菌是人类皮肤和粘膜微生物群中普遍存在的成员。在功能上，它 是通过免疫调节和微生物群落稳态对人类健康的关键贡献者。然而 “阿克萨尔”表皮葡萄球菌也是一种重要的病原体和疾病风险因子， 医疗器械和血液感染的原因。多个遗传上不同的亚种或品系， 色葡萄表皮细胞可以与具有可变基因含量的基因组共同居住在皮肤上。绝大多数 这些基因具有未知的功能。我们假设这个可变的基因内容，或辅助基因组， 与核心基因相互作用，使菌株能够独特地应对不同的环境并在其中茁壮成长， 这些遗传多样性菌株的混合对于维持皮肤中的健康稳态是必要的。到 研究这些基因的功能，并了解菌株水平的遗传多样性如何有助于 群体水平的表型，我们将在功能上分析一组遗传多样性菌株分离自 健康个体和患有血流感染的个体。我们将创建CRISPRi工具， 在S.系统地鉴定菌株特异性和核心基因的能力， 在皮肤和感染中定植和竞争。目的1开发CRISPRi基因工具包， S. epidermidis敲低池。对这些样本池进行表型分析将大大扩展我们对 一个共同的微生物伴侣所采用的重要的生物学策略，以及遗传异质性如何 可能会影响到从口腔到感染的转变。目的2研究应变外加剂在这一过程中的作用 过渡这种基因组方法和机制研究的结合将提供第一次调查 S的功能。表皮泛基因组注释菌株间的遗传多样性将揭示新的 深入了解菌株多样性的功能后果：菌株如何成功地在 细菌和毒力的生活方式，以及多种菌株如何在生态网络中共存。