Mechanisms of anti-phage defenses and their mobilization in staphylococci

葡萄球菌中的抗噬菌体防御机制及其动员

• 批准号: 10563748
• 负责人: Asma HATOUM
• 金额: $ 49.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563748
• 关键词: Address; Antibiotic Resistance; Antibiotics; Bacteria; Bacteriophages; Binding Sites; Biochemical; Bioinformatics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Development; Distal; Effectiveness; Environmental Risk Factor; Excision; Genes; Genetic; Genetic Recombination; Genome; Genomic Islands; Genomic Segment; Genomics; Genus staphylococcus; Goals; Horizontal Gene Transfer; Human; Immune system; Immunity; Infection; Innate Immune System; Knowledge; Light; Lytic; Maps; Mediating; Medical Device; Methicillin Resistance; Molecular; Operon; Organism; Pathogenesis; Pathogenicity; Pathogenicity Island; Pathway interactions; Regulon; Research; Site; Skin; Skin Tissue; Soft Tissue Infections; Source; Staphylococcus Phages; Staphylococcus aureus; Staphylococcus epidermidis; System; Testing; Therapeutic; Toxin; Virulence; Virulence Factors; Virus; Work; antibiotic resistant infections; care outcomes; combat; community setting; fitness; genetic approach; genomic locus; health care settings; helicase; improved; insight; model organism; novel; nuclease; overexpression; recombinase; skin microbiome; stem; therapeutically effective

Project Summary Staphylococci are ubiquitous bacterial residents of human skin and major causes of antibiotic-resistant infections. Of the ~40 skin-associated species, S. aureus and S. epidermidis have the greatest pathogenic potential: S. aureus is the leading cause of skin and soft tissue infections and S. epidermidis is the most common cause of infections associated with indwelling medical devices. Compounding the problem, S. epidermidis strains harbor a reservoir of genes that enhance fitness/virulence (e.g. genes that encode toxins and antibiotic resistance) which can be horizontally transferred to S. aureus. In light of these facts, a thorough understanding of the mechanisms that regulate horizontal gene transfer between these species would be an invaluable asset in neutralizing or stemming the flow of these factors at the source. In this context, staphylococcal phages (i.e. viruses) and the immune systems targeted against them have profound impacts on staphylococcal survival and pathogenesis. For instance, lysogenic phages can enhance pathogenic potential by transferring pathogenicity islands from one strain to another and carrying virulence factors that integrate along with the phage genome into the host. In contrast, strictly lytic phages can kill the bacterial host within minutes and are being used as alternative therapeutics to combat antibiotic-resistant infections. Bacterial immune systems target lytic and lysogenic phages alike, and can therefore counter these opposing effects. As it stands, we are only just beginning to understand these dynamics and identify the specific immune systems that staphylococci employ, and alarmingly, almost nothing is known about how these systems are horizontally spread. These knowledge gaps continue to undermine our ability to implement effective therapeutics and improve overall healthcare outcomes. The long-term objective of this R01 project is to gain a comprehensive understanding of the anti-phage immune systems in staphylococci and the pathways by which they spread. Towards this goal, this research uses S. epidermidis and a collection of diverse phages as model organisms to achieve three specific aims: Aim 1 will identify and characterize new anti-phage defenses in a suite of S. epidermidis clinical isolates using genetics, biochemical, and bioinformatics approaches. Aim 2 will determine the major genetic and environmental factors that drive mobilization of these defenses using molecular and genetic approaches. Aim 3 seeks to determine the global impacts of the molecular machinery that mediate defense mobilization using high-throughput genetics approaches. By revealing new insights into mechanisms of anti-phage defenses in staphylococci and the pathways by which they spread, the proposed work will enable the development of more effective approaches for not only combatting the spread of resistance to antibiotics but also saving the burgeoning phage therapeutics from a similar fate. This work will also open up exciting new research directions in understanding staphylococci and other organisms that harbor similar systems.

项目摘要 葡萄球菌是人体皮肤中普遍存在的细菌，也是产生抗生素耐药性的主要原因 感染。在约40种与皮肤有关的物种中，金黄色葡萄球菌和表皮葡萄球菌的致病性最强。 潜在的：金黄色葡萄球菌是皮肤和软组织感染的主要原因，表皮葡萄球菌是最常见的 与留置医疗器械相关的感染原因。使问题复杂化的是，表皮葡萄球菌菌株 存放增强适合性/毒性的基因(例如编码毒素和抗生素的基因 抗性)，可水平转移给金黄色葡萄球菌。鉴于这些事实，彻底了解 控制这些物种之间水平基因转移的机制将是一笔无价的财富 在源头上中和或阻止这些因素的流动。在这方面，葡萄球菌噬菌体(即 病毒)和针对它们的免疫系统对葡萄球菌的生存和 发病机制。例如，溶原噬菌体可以通过转移致病性来增强致病潜能。 从一个菌株到另一个菌株的岛屿，携带的毒力因子与噬菌体基因组一起整合到 主持人。相比之下，严格溶解的噬菌体可以在几分钟内杀死细菌宿主，并被用作 对抗抗药性感染的替代疗法。细菌免疫系统靶向溶血素和 溶原噬菌体相似，因此可以对抗这些相反的作用。就目前情况而言，我们才刚刚开始 为了了解这些动态并确定葡萄球菌使用的特定免疫系统，以及 令人担忧的是，关于这些系统是如何水平传播的，人们几乎一无所知。这些知识差距 继续削弱我们实施有效疗法和改善整体医疗结果的能力。 R01项目的长期目标是全面了解抗噬菌体免疫 葡萄球菌中的系统及其传播途径。为了实现这一目标，本研究采用了S. 表皮和一系列不同的噬菌体作为模式生物，以实现三个具体目标：目标1将 利用遗传学在一组表皮葡萄球菌临床分离株中识别和表征新的抗噬菌体防御系统， 生物化学和生物信息学的方法。目标2将确定主要的遗传和环境因素 使用分子和遗传方法来推动这些防御系统的动员。目标3试图确定 利用高通量遗传学调节国防动员的分子机制的全球影响 接近了。通过揭示葡萄球菌抗噬菌体防御机制的新见解和 关于它们传播的途径，拟议的工作将使制定更有效的办法成为可能。 不仅是为了对抗抗生素耐药性的传播，也是为了拯救蓬勃发展的噬菌体疗法 脱离了类似的命运。这项工作还将在了解葡萄球菌方面开辟令人兴奋的新研究方向 以及其他拥有类似系统的生物体。