Structural basis for mobilization of S. aureus pathogenicity islands

金黄色葡萄球菌致病岛动员的结构基础

• 批准号: 8975434
• 负责人: Terje Dokland
• 金额: $ 42.09万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975434
• 关键词: Animals; Antibiotic Resistance; Antibiotics; Bacteriophages; Biochemical; Capsid; Capsid Proteins; Cells; Communities; Cytolysis; DNA Maintenance; DNA Packaging; Dependency; Evolution; Frequencies; Genes; Genetic; Genome; Growth; Horizontal Gene Transfer; Human; Infection; Integration Host Factors; Light; Lytic; Methods; Minor; Mobile Genetic Elements; Modeling; Morphogenesis; Pathogenicity; Pathogenicity Island; Pathway interactions; Peptide Hydrolases; Population; Process; Production; Property; Proteins; Public Health; Research; Resistance; Resolution; Role; Scaffolding Protein; Specificity; Staphylococcus aureus; Structural Protein; Structure; Superantigens; Surface Plasmon Resonance; System; Therapeutic Uses; Toxin; Virulence; Virulence Factors; Virulent; base; biological systems; derepression; genetic element; macromolecular assembly; mutant; overexpression; particle; pathogen; progenitor; protein expression; public health relevance; resistant strain; scaffold; sensor; terminase

 DESCRIPTION (provided by applicant): Staphylococcus aureus is an opportunistic pathogen that is associated with a range of serious pathogenic conditions in humans and animals. The emergence of virulent, community-acquired S. aureus strains that are resistant to many antibiotics has become a significant public health problem. Many virulence determinants in S. aureus are carried on mobile genetic elements, including S. aureus pathogenicity islands (SaPIs) that carry genes encoding virulence factors such as superantigen toxins. SaPIs are normally stably integrated into the host genome, but become mobilized by specific helper phages, such as 80a or fNM1, resulting in the packaging of the SaPI genome into phage-like transducing particles that are made from helper-encoded structural proteins. The SaPIs have evolved the ability to sense the presence of a lytic phage, exploit phage functions and interfere with phage multiplication. This interference includes altered dependency on phage functions, specific selection of SaPI DNA for packaging, and the formation of capsids that are too small to package phage genomes. The resulting particles can transfer virulence factors to other cells, even across genera, at high frequency. The overall aim of the current project is to understand the structural basis for SaPI mobilization, helper-SaPI specificity, and the factors involved in their spread and establishment. Such processes are important factors in S. aureus evolution and pathogenicity. Specifically, we aim to: (1) Define the roles of the 80a scaffolding protein in capsid assembly; (2) Determine the mechanism of SaPI-induced capsid size redirection; (3) Establish the role of gp44 in DNA packaging and stability; and (4) Understand the process of SaPI derepression by helper phage dUTPases. These aims focus on different aspects of the mobilization process and will be studied by a combination of genetic, biochemical and structural methods. Elucidation of these mechanisms will have significant implications for understanding the role of phages, SaPIs and other mobile genetic elements in the spread and establishment of virulence determinants in S. aureus. In addition, this research will aid our understanding of macromolecular assembly processes and capsid size determination in general.

 描述（由申请方提供）：金黄色葡萄球菌是一种机会致病菌，与人类和动物的一系列严重致病性疾病相关。社区获得性致病性S。对许多抗生素具有抗性的金黄色葡萄球菌菌株已经成为重要的公共卫生问题。S.金黄色葡萄球菌携带在移动的遗传元件上，包括S.金黄色葡萄球菌致病岛（SaPI）携带编码毒力因子的基因，如超抗原毒素。SaPI通常稳定地整合到宿主基因组中，但被特异性辅助蛋白如80 a或fNM 1动员，导致SaPI基因组包装到由辅助蛋白编码的结构蛋白制成的噬菌体样转导颗粒中。SaPI已经进化出感测裂解性噬菌体的存在、利用噬菌体功能和干扰噬菌体增殖的能力。这种干扰包括改变对噬菌体功能的依赖性，特异性选择用于包装的SaPI DNA，以及形成太小而不能包装噬菌体基因组的衣壳。由此产生的颗粒可以高频率地将毒力因子转移到其他细胞，甚至跨属转移。 当前项目的总体目标是了解SaPI动员的结构基础，辅助SaPI特异性，以及参与其传播和建立的因素。这些过程是S.金黄色葡萄球菌的进化和致病性。具体而言，我们的目标是：（1）定义80 a支架蛋白在 衣壳组装;（2）确定SaPI诱导的衣壳大小重定向的机制;（3）确定gp 44在DNA包装和稳定性中的作用;（4）理解辅助噬菌体dUTPases对SaPI去阻遏的过程。 这些目标侧重于动员过程的不同方面，并将通过遗传、生物化学和结构方法相结合的方式进行研究。阐明这些机制将对了解噬菌体、SaPI和其他移动的遗传元件在S.金黄色。此外，这项研究将有助于我们了解大分子组装过程和衣壳大小的测定一般。