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 葡萄球菌是人类皮肤的普遍细菌居民，是抗生素耐药性的主要原因 感染。在约40种皮肤相关的物种中，金黄色葡萄球菌和表皮链球菌具有最大的致病性 潜力：金黄色葡萄球菌是皮肤和软组织感染的主要原因，表皮链球菌是最常见的 与留置医疗设备相关的感染原因。 s。表皮菌株使问题更加复杂 藏有增强适应性/毒力的基因储层（例如编码毒素和抗生素的基因 电阻）可以水平转移到金黄色葡萄球菌。鉴于这些事实，彻底理解 调节这些物种之间水平基因转移的机制将是宝贵的资产 在中和或阻止这些因素的流动中。在这种情况下，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存活有深远的影响 发病。例如，溶裂性噬菌体可以通过转移致病性来增强致病潜力 从一个菌株到另一个菌株，并携带与噬菌体基因组一致整合到的毒力因子 主人。相反，严格裂解噬菌体可以在几分钟内杀死细菌宿主，并用作 替代抗生素耐药感染的替代疗法。细菌免疫系统靶向裂解和 溶菌发生噬菌体，因此可以应对这些相反的作用。就目前而言，我们才刚刚开始 了解这些动态并确定葡萄球菌采用的特定免疫系统，以及 令人震惊的是，这些系统如何水平传播几乎一无所知。这些知识差距 继续破坏我们实施有效治疗剂并改善整体医疗保健结果的能力。 该R01项目的长期目标是获得对抗衰老免疫的全面理解 葡萄球菌中的系统及其传播的途径。为了实现这一目标，这项研究使用了。 表皮和一系列不同的噬菌体作为模型生物，以实现三个特定目标：AIM 1将 使用遗传学，识别并表征一组表皮链球菌临床分离株中新的抗流量防御措施， 生化和生物信息学方法。 AIM 2将确定主要的遗传和环境因素 通过分子和遗传学方法，这可以驱动这些防御。 AIM 3试图确定 使用高通量遗传学介导防御动员的分子机制的全球影响 方法。通过揭示对葡萄球菌和抗流量防御机制的新见解和 他们传播的途径，拟议的工作将使开发更有效的方法 不仅要打击抗生素耐药性的传播，还可以节省蓬勃发展的噬菌体治疗剂 来自类似的命运。这项工作还将为理解葡萄球菌开辟令人兴奋的新研究方向 以及具有类似系统的其他生物。