Virulence gene regulation in Staphylococcus aureus

 描述(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，但这种微生物仍在医院和社区环境中造成显著的发病率和死亡率。该菌的致病力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控因子的调节，形成了一个复杂的调控网络。阐明金黄色葡萄球菌的毒力调控机制是了解其致病机制的关键。然而，尽管进行了密集的努力，这种病原体如何协调控制其大量毒力基因以成功感染，在很大程度上仍不清楚。因此，本研究的长期目标是了解金黄色葡萄球菌的毒力基因调控。在我们的实验室中，我们已经使用特征良好的衣壳作为模式毒力因子来了解金黄色葡萄球菌毒力基因的调控。衣壳是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宿主正确相互作用所需的重要细胞表面成分。因此，胶囊需要受到细菌的仔细监管。我们之前已经在分子水平上详细描述了负责胶囊生物合成的帽子操纵子。我们和其他人随后进行的研究表明，有许多调节剂影响胶囊的生产。有趣的是，我们发现其中几个调控因子并不是典型的转录调控因子，这表明其中涉及到新的调控机制。此外，许多影响衣壳的调控因子已被证明影响其他毒力因子，如毒素，这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 用分子和生物化学方法研究新型调节剂调控胶囊的基本机制。在第二个具体目标中，我们将使用遗传学方法来研究胶囊是如何受到调控网络的调控，以及另一个重要的毒力因子-胶囊和a-毒素如何受到共同调控的差异调控。大多数毒力基因调控研究都是在实验室条件下方便地在体外进行的。对体内感染过程中的毒力调节知之甚少。因此，在最后一个具体目标中，我们将进行动物研究，以了解毒力基因在体内的调控，使用两个非常不同的动物模型，代表由金黄色葡萄球菌引起的两种不同的常见疾病。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，从而为开发治疗葡萄球菌感染的新疗法提供坚实的基础。

 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.