Structural basis for pathogenicity island mobilization in S. aureus

金黄色葡萄球菌致病岛动员的结构基础

• 批准号: 7901402
• 负责人: Terje Dokland
• 金额: $ 36.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901402
• 关键词: Address; Am 80; Antibiotic Resistance; Bacterial Genome; Bacteriophages; Biochemical; Capsid; Cells; DNA; Development; Discrimination; Elements; Enterotoxins; Evolution; Family; Genes; Genetic; Genome; Genus staphylococcus; Health; Hospitals; Indigenous; Infection; Light; Mass Spectrum Analysis; Medical; Methods; Pathogenesis; Pathogenicity; Pathogenicity Island; Pathway interactions; Peptide Hydrolases; Population; Population Research; Production; Prophages; Proteins; Public Health; Role; Scaffolding Protein; Staphylococcus aureus; Structural Genes; Structural Protein; System; Systemic infection; Therapeutic Uses; Toxic Shock Syndrome; Toxic Shock Syndrome Toxin-1; Toxin; X-Ray Crystallography; base; genetic element; interest; member; particle; public health relevance; reconstruction; resistant strain; scaffold; terminase

DESCRIPTION (provided by applicant): Staphylococcus aureus produces a number of toxins of great medical importance, including toxic shock syndrome toxin (TSST-1) and enterotoxins B and C. Several of these toxins are carried on so-called pathogenicity islands (SaPIs), genetic elements that resemble prophages, but lack most of the genes normally associated with phage production. These elements are normally stable, but can be mobilized by infection with certain phages or by the induction of indigenous prophages, upon which the SaPIs get excised and packaged into phage-like particles that can transfer the toxin genes to new cells. The type member of the SaPI family, SaPI1 can be mobilized by phage 80? and is efficiently packaged into phage-like particles using 80? structural proteins. However, the SaPI1 capsid is only 1/3 the size of the normal 80? capsid, commensurate with its smaller genome. With the emergence of antibiotic-resistant Staphylococcus strains and the renewed interest in therapeutic use of bacteriophages to treat such infections, the phage-induced mobilization of SaPI1 will be an important consideration. The overall objective of this study is to understand the structural basis for the phage-induced mobilization and spread of S. aureus pathogenicity islands and its role in the development of bacterial pathogenesis. In this project, we address two specific questions in relation to the SaPI1 mobilization: How does SaPI1 induce the formation of small capsids from 80?-encoded proteins? How is the SaPI1 DNA selected for packaging into these capsids? Understanding these questions will have a bearing on understanding the evolution of pathogenicity in S. aureus. To this end, we will use a combination of genetic, biochemical and structural approaches, including cryo-EM, X-ray crystallography and Mass Spectrometry. The specific aims of this study are: (1) Define the role of the 80? structural gene products in capsid formation (2) Determine the mechanism of SaPI1-induced capsid size determination (3) Identify the determinants for DNA discrimination by SaPI1. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus has become a major health problem in hospitals, especially with the emergence of multiple antibiotic resistant strains. Pathogenic S. aureus may cause severe systemic infections by producing several toxins from genes carried on so-called pathogenicity islands in the bacterial genome. The bacteriophage/pathogenicity island system under study in this project is of special interest for its role in the horizontal spread and long-term establishment of pathogenicity in the population.

性状（由申请方提供）：金黄色葡萄球菌产生许多具有重要医学意义的毒素，包括中毒性休克综合征毒素（TSST-1）和肠毒素B和C。这些毒素中有几种是在所谓的致病岛（SaPI）上携带的，这些致病岛是类似于噬菌体的遗传元件，但缺乏通常与噬菌体生产相关的大多数基因。这些元素通常是稳定的，但可以通过感染某些细菌或通过诱导土著原噬菌体来动员，在此基础上，SaPI被切除并包装成噬菌体样颗粒，可以将毒素基因转移到新细胞中。型成员的SaPI家族，SaPI 1可以动员噬菌体80？并有效地包装成噬菌体样颗粒使用80？结构蛋白然而，SaPI 1衣壳的大小只有正常80？衣壳，与其较小的基因组相称。随着耐药性葡萄球菌菌株的出现和噬菌体治疗此类感染的治疗用途的重新关注，噬菌体诱导的SaPI 1动员将是一个重要的考虑因素。本研究的总体目标是了解噬菌体诱导的S.金黄色葡萄球菌致病岛及其在细菌致病过程中的作用。在这个项目中，我们解决了两个具体的问题有关的SaPI 1动员：如何SaPI 1诱导形成小衣壳从80？-编码蛋白质？如何选择SaPI 1 DNA包装到这些衣壳中？理解这些问题将有助于理解沙门氏菌致病性的进化。金黄色。为此，我们将使用遗传，生物化学和结构方法的组合，包括cryo-EM，X射线晶体学和质谱。本研究的具体目的是：（1）明确80后的角色定位;（2）确定SaPI 1诱导的衣壳大小决定的机制（3）确定SaPI 1识别DNA的决定因素。公共卫生相关性：金黄色葡萄球菌已成为医院的主要健康问题，特别是随着多种抗生素耐药菌株的出现。致病性S.金黄色葡萄球菌可通过从细菌基因组中所谓的致病岛上携带的基因产生几种毒素而引起严重的全身感染。本项目研究的噬菌体/致病岛系统因其在水平传播和长期建立种群致病性中的作用而特别令人感兴趣。