Genetic regulation of staphylococcal capsule

金黄色葡萄球菌是人类的主要病原体，可引起严重感染。这个 由于新出现的多重耐药，生物体最近变得越来越有问题 对抗生素治疗无效的菌株。因此，新的治疗方法 急需之物。几乎所有的金黄色葡萄球菌菌株都能产生荚膜多糖，这种多糖已经被 可分为11个集合型。5型和8型胶囊，在结构和遗传上相似， 是主要的胶囊，因此被用作疫苗开发的靶标。近期 包括我们自己在内的研究表明，这些胶囊起到了抗吞噬毒性因子的作用。 从而在葡萄球菌的发病机制中发挥重要作用。这些产品的生产 胶囊受环境刺激的影响，但对其调控知之甚少。 在分子水平上。最近，我们已经确定了控制该基因的启动子区域。 表达8型胶囊基因，并表明5型和8型胶囊受 几个已知的监管机构。我们还从基因上鉴定了几个可能的调控基因。 因此，这些结果表明，5型和8型胶囊受复杂的调控 网络。在这项提案中，我们将重点关注胶囊表达的调控方面。我们建议 实现三个具体目标：(I)确定参与控制的调控基因 用分子方法生产胶囊；(Ii)研究调节剂之间的相互作用 调控基因缺失突变体的遗传和生化分析以阐明调控 联网；(3)调查环境刺激对胶囊的调节，重点是 二氧化碳在体外和体内都有作用。顺利完成下列研究 这一应用无疑将揭开控制这些基因表达的调控机制 重要的毒力因子，这将为开发新的治疗方法提供坚实的基础 葡萄球菌感染。

Staphylococcus aureus is a major human pathogen, which can cause serious infections. The organism has become increasingly problematic recently due to emerging multiple-drug resistance strains that are unresponsive to antibiotic treatment. New methods of treatment are therefore urgently needed. Almost all strains of S. aureus produce capsular polysaccharide, which have been classified into 11 setotypes. Type 5 and 8 capsules, which are structurally and genetically similar, are predominant capsules and thus have been used as targets for vaccine development. Recent studies, including our own, have shown that these capsules act as antiphagocytic virulence factors and thereby play an important role in staphylococcal pathogenesis. The produciton of these capsules are influenced by environmental stimuli, however, very little is known about their regulation at the molecular level. Recently, we have characterized the promoter region controlling the expression type 8 capsule genes and have shown that type 5 and 8 capsules are regulated by several known regulators. We have also genetically identified several putative regulatory genes. These results therefore suggest that type 5 and 8 capsules are regulated by a complex regulatory network. In this proposal, we will focus on the regulatory aspect of capsule expression. We propose to accomplish three specific aims: (i) to characterize the regulatory genes involved in the control of capsule production by molecular approaches; (ii) to study the interactions between regulators by genetic and biochemical analyses of mutants deficient in regulatory genes to elucidate regulatory networking; (iii) to investigate the regulation of capsules by environmental stimuli by focusing on carbon dioxide effect both in vitro and in vivo. The successful completion of the studies outlined in this application will undoubtedly unveil the regulatory mechanism controlling the expression of these important virulence factors, which will provide a firm basis for developing new methods of treating staphylocuccal infections.