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: 10328966
• 负责人: Julia S Oh
• 金额: $ 62.68万
• 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: 2021-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328966
• 关键词: Address; Admixture; Affect; Bacteria; Behavior; Candidate Disease Gene; Characteristics; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Disease; Ecosystem; Environment; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genomic approach; Goals; Growth; Guide RNA; Health; Health Promotion; Homeostasis; Human; Immune system; In Vitro; Individual; Infection; Infection prevention; Infectious Skin Diseases; Inflammation; Investigation; Knowledge; Life Style; Medical Device; Metabolism; Methods; Molecular; Mucous Membrane; Pathogenicity; Patients; Phenotype; Phylogenetic Analysis; Physiology; Population; Positioning Attribute; Process; Public Health; RNA Sequences; Regulation; Repression; Role; Sepsis; Site; Skin; Skin colonization; Staphylococcus epidermidis; Testing; Therapeutic; Virulence; base; design; disorder risk; experimental study; fitness; gene function; gene network; genetic architecture; genetic strain; genome-wide; immunoregulation; improved; in vivo; insight; knock-down; medical implant; member; microbial; microbial community; mucosal microbiota; pan-genome; pathogen; prevent; screening; skin disorder; skin microbiome; skin microbiota; success; tool; whole genome

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.

项目摘要 /摘要 表皮葡萄球菌是人类皮肤和粘膜微生物群的普遍成员。在功能上，它 是通过免疫调节和微生物社区稳态来促进人类健康的关键因素。但是 “ Comensal” S. epidermidis也是重要的病原体和疾病风险库，这是最常见的 医疗装置和血液感染的原因。多种系统发育的亚种或菌株， 表皮链球菌可以与可变基因含量的基因组共同居住皮肤。绝大多数 这些基因具有未知的功能。我们假设该变量基因含量或附属基因组， 与核心基因相互作用，使菌株能够在不同的环境中唯一响应和繁荣 这些一般多种菌株的混合对于维持皮肤健康的稳态是必要的。到 研究这些基因的功能，并了解应变水平下的遗传多样性如何有助于 人口级表型，我们将在功能上介绍一组从 健康的个体和患有血液感染的个体。我们将为基因创建CRISPRI工具 表皮链球菌的敲低以系统地识别菌株特异性和核心基因，这些基因的能力是 在皮肤和感染中殖民并竞争。 AIM 1开发了CRISPRI基因工具包来创建的 S. epidermidis敲低池。表型分析这些池将大大扩展我们对 普通微生物伴侣采用的重要共生策略以及遗传异质性 可能会影响传染性过渡的共生。 AIM 2研究了菌株混合在此中的作用 过渡。基因组方法和机理研究的这种结合将提供首次研究 进入表皮链球菌的功能。注释的材料间遗传多样性将揭示新的 对应变多样性的功能后果的见解：菌株如何成功过渡 共生和病毒的生活方式，以及多种菌株如何在生态网络中共存。