Capsule regulatory network in S. aureus pathogenesis

金黄色葡萄球菌是一种人类病原体，可导致严重疾病。这种有机体是 不断进化，毒力更强，对抗生素更具抗药性的菌株 近几年才出现的。因此，由这种微生物引起的感染已经成为 越来越难治疗。因此，迫切需要新的治疗方法。S. 金黄色葡萄球菌的致病性取决于有机体产生的过多毒力因子， 它们由同样多的监管机构在一个令人惊讶的复杂的 一种远未被理解的举止。了解毒力调节是 了解发病机制，这是为发展提供基础知识所必需的 新的治疗方法。大多数金黄色葡萄球菌菌株产生一种类型的包膜 类型5或类型8的多糖。由于它们的优势，这些胶囊 一直是疫苗开发的主要组成部分。最近的动物研究使用了各种不同的 模型已经明确地表明，5型和8型胶囊作为一种 葡萄球菌致病机制中的抗吞噬因子。然而，像其他毒力因素一样，几乎没有 已经知道这些胶囊的调节，特别是在体内。最近，我们已经确定了 并对影响胶囊生产的几种调节剂进行了表征。我们的研究表明， 5和8胶囊由更多的监管机构监管，其中大多数也监管 其他致病因素。根据这些结果，我们假设胶囊受到高度调控 通过一个复杂的调控网络来响应各种环境中的细菌 在发病过程中相遇。值得注意的是，其中一些监管机构并不常见 作为转录调控因子，可能涉及一种不常见的调控模式。 因此，在这项建议中，我们将重点阐明胶囊的调控机制 作为了解金黄色葡萄球菌毒力基因调控的体外和体内模型。我们建议 实现三个具体目标：(I)确定影响胶囊的调控网络的特征 生产；(Ii)阐明调节机制；(Iii)调查 并将毒力基因调控与致病机制联系起来。成功者 完成本申请中概述的研究不仅将提供对 胶囊的调节也将有助于我们对其整体机制的理解 毒力基因调控。从这些研究中获得的新知识将为 为开发控制葡萄球菌感染的新方法奠定了基础。

Staphylococcus aureus is a human pathogen that can cause serous illnesses. The organism is constantly evolving and strains that are more virulent and more resistant to antibiotics have emerged in recent years. As a result, the infections caused by this organism have become increasingly difficult to treat. New methods of treatment are therefore urgently needed. S. aureus pathogenicity depends on a plethora of virulence factors produced by the organism, which are regulated by an equally impressive number of regulators in a surprisingly complex manner that is far from been understood. Understanding virulence regulation is the key to understand pathogenesis, which is needed for providing fundamental knowledge for developing new methods of treatment. Most strains of S. aureus produce one type of capsular polysaccharide that is either type 5 or type 8. Because of their predominance these capsules have been the prime components for vaccine development. Recent animal studies using various models have unequivocally shown that type 5 and type 8 capsules play an important role as an antiphagocytic factor in staphylococcal pathogenesis. However, like other virulence factors, little is known about the regulation of these capsules especially in vivo. Recently, we have identified and characterized several regulators affecting capsule production. Our studies indicate that type 5 and 8 capsules are regulated by a larger number of regulators most of which also regulate other virulence factors. Based on these results, we hypothesize that capsule is highly regulated by a complex regulatory network in responding to various environments that the bacteria encounter during pathogenesis. It is worth noting that some of these regulators are uncommon as a transcriptional regulator suggesting an uncommon mode of regulation may be involved. Accordingly, in this proposal, we will focus on elucidating capsule regulatory mechanisms in vitro and in vivo as a model to understand virulence gene regulation in S. aureus. We propose to accomplish three specific aims: (i) to characterize the regulatory network affecting capsule production; (ii) to elucidate the mechanisms of regulation; (iii) to investigate the regulation of capsule in vivo and to relate virulence gene regulation to pathogenesis. The successful completion of the studies outlined in this application not only will provide further insight on capsule regulation but also will contribute to our understanding of the overall mechanism of virulence gene regulation. The new knowledge gained from these studies will provide a firm basis for developing novel methods for controlling staphylococcal infections.