Virulence gene regulation in Staphylococcus aureus

金黄色葡萄球菌毒力基因调控

• 批准号: 8912102
• 负责人: Chia Y. Lee
• 金额: $ 24.83万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912102
• 关键词: 5' Untranslated Regions; ATP phosphohydrolase; Abscess; Address; Affect; Anabolism; Animal Model; Animals; Bacteria; Biochemical; Cell surface; Complex; Cues; DNA Binding; Development; Disease; Environment; Gene Expression Regulation; Genes; Genus staphylococcus; Goals; Healthcare; Hospitals; Human; Immune system; In Vitro; Infection; Infective endocarditis; Investments; Knowledge; Laboratories; Lead; Life; Masks; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Operon; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Prevention strategy; Process; Production; Publishing; RNAIII; Rattus; Regulation; Reporting; Research; Role; Signal Transduction; Small RNA; Solid; Staging; Staphylococcal Infections; Staphylococcal Protein A; Staphylococcus aureus; System; Toxin; Variant; Virulence; Virulence Factors; Virulent; base; capsule; community setting; genetic approach; human tissue; in vivo; insight; mortality; novel; novel therapeutics; pathogen; public health relevance; response; subcutaneous; treatment strategy

 DESCRIPTION (provided by applicant): Staphylococcus aureus is an important human pathogen capable of causing infections in virtually all human tissues. The organism continues to cause significant morbidity and mortality in hospital and community settings despite huge investments in healthcare. The pathogenicity of this organism is dependent on its ability to produce various virulence factors, which are regulated by a large number of regulators forming a complex regulatory network. Elucidation of virulence regulation is crucial to understand pathogenesis of S. aureus. However, despite intensive efforts, how this pathogen coordinately controls its large number of virulence genes for a successful infection is still largely unknown. Thus, the long-term goal of this research is to understand virulence gene regulation in S. aureus. In our laboratory, we have employed the well-characterized capsule as a model virulence factor to understand virulence gene regulation in S. aureus. Capsule is an important virulence factor that endows the bacteria to resist host immune system but it also masks important cell surface components required for proper interactions of the bacteria with its host. Capsule therefore needs to be carefully regulated by the bacteria. We have previously characterized the cap operon responsible for capsule biosynthesis in detail at the molecular level. Subsequent studies conducted by us and others have shown that there are many regulators affecting capsule production. Interestingly, we found that several of these regulators are not typical transcriptional regulators suggesting that novel regulatory mechanisms are involved. In addition, many regulators affecting capsule have been shown to affect other virulence factors, such as toxins, suggesting that extensive interactions exists between regulatory networks of different virulence factors. Accordingly, in the first Specific Aim, we will study the fundamental mechanisms involved in capsule regulation by novel regulators using molecular and biochemical approaches. In the second Specific Aim, we will use genetic approaches to study how capsule is regulated by a network of regulators and how capsule and a-toxin, another important virulence factor, are differentially regulated by common regulators. Most virulence gene regulation studies have been conveniently carried out under laboratory conditions in vitro. Little is known about virulence regulation during an in vivo infection. Thus, n the last Specific Aim, we will carry out animal studies to understand virulence gene regulation in vivo using two very different animal models representing two different common diseases caused by S. aureus. We believe that successful completion of these proposed studies will provide new insights into virulence gene regulation in S. aureus thereby providing a firm basis to develop novel therapeutics to treat staphylococcal infections.

 描述（由申请人提供）：金黄色葡萄球菌是一种重要的人类病原体，能够在几乎所有人体组织中引起感染，尽管在医疗保健方面进行了巨大的投资，但该生物体仍然在医院和社区环境中造成显着的发病率和死亡率。依赖于其产生各种毒力因子的能力，这些毒力因子受到大量调节因子的调节，形成复杂的调节网络，阐明毒力调节对于了解金黄色葡萄球菌的发病机制至关重要。然而，尽管付出了巨大的努力，这种病原体如何协调控制其大量毒力基因以实现成功感染仍然很大程度上未知，因此，这项研究的长期目标是了解金黄色葡萄球菌的毒力基因调控。我们的实验室采用了已充分表征的荚膜作为模型毒力因子来了解金黄色葡萄球菌的毒力基因调控。荚膜是终止细菌抵抗宿主免疫系统的重要毒力因子。但它也掩盖了细菌与其宿主正确相互作用所需的重要细胞表面成分，因此我们之前在分子水平上详细描述了负责胶囊生物合成的帽操纵子。我们和其他人进行的研究表明，有许多监管机构会影响其他胶囊的生产。毒力因子，例如毒素，表明不同毒力因子的调控网络之间存在广泛的相互作用。因此，在第一个具体目标中，我们将。 使用分子和生化方法研究新型调节剂参与胶囊调节的基本机制在第二个具体目标中，我们将使用遗传方法来研究调节剂网络如何调节胶囊以及胶囊和α-毒素（另一种重要的毒力）如何。大多数毒力基因调控研究都是在体外实验室条件下方便地进行的，因此，在最后一个具体目标中，我们对体内感染过程中的毒力调控知之甚少。使用代表金黄色葡萄球菌引起的两种不同常见疾病的两种截然不同的动物模型进行动物研究，以了解体内毒力基因调控。我们相信，这些拟议研究的成功完成将为金黄色葡萄球菌毒力基因调控提供新的见解。为开发治疗葡萄球菌感染的新疗法奠定了坚实的基础。