Regulation of hyaluronic acid capsule biosynthesis in Streptococcus pyogenes

描述(由申请人提供)： 化脓性链球菌是一种重要的人类病原体，可引起多种疾病，从皮肤和咽部的轻微感染(如脓疱病和咽炎)到危及生命的侵袭性感染(如链球菌中毒综合征和坏死性筋膜炎)。在世界范围内，气体感染每年导致超过6亿例咽炎和超过65万例侵袭性疾病。自20世纪80年代末以来，侵袭性气体疾病在全球范围内有所增加。虽然这种病原体对抗生素治疗很敏感，但严重的侵袭性气体感染往往很难治疗。透明质酸(HA)胶囊被认为是毒力的主要决定因素之一。高度包膜的气体菌株与侵袭性感染和急性风湿热爆发有关。在GAS感染小鼠模型中，无被膜的GAS突变株对中性粒细胞的杀伤敏感，并降低了毒力。除了它在细菌耐药性中的作用外 为了防御攻击，HA胶囊调节粘连并促进咽部气体定植。胶囊的表达需要有效和灵敏的调控机制，以避免过度的胶囊过度生产。在目前的模型中，COVR与由hasABC基因组成的has囊膜基因操纵子的启动子区域结合并抑制其转录。然而，这一机制的细节大多不清楚。这项研究的主要目的是了解HA胶囊调节的分子机制。在我们的初步研究中，我们发现了一个控制衣壳操纵子转录的新的非编码区。我们证实，该区域具有重要的生理意义，对于气体侵袭性疾病的小鼠模型的完全毒力是重要的。此外，我们发现该区域处于很强的选择压力下，导致GAS临床菌株中自发突变的积累。我们建议使用先进的遗传和生化技术来定义这种新的胶囊调节机制。这项研究的结果有望对气体感染暴发期间的诊断分析和控制侵袭性气体疾病的高度针对性的治疗方法的发展产生积极影响。

DESCRIPTION (provided by applicant): Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen that causes numerous diseases ranging from minor skin and throat infections such as impetigo and pharyngitis to life-threatening invasive infections such as streptococcal toxic syndrome and necrotizing fasciitis. Worldwide GAS infections account for more than 600 million cases of pharyngitis and more than 650,000 cases of invasive disease annually. Since the late 1980s, there has been a worldwide increase in invasive GAS disease. Although the pathogen is susceptible to antibiotic therapy, severe invasive GAS infections are often difficult to treat. Hyaluronic acid (HA) capsule is considered one of the major determinants of GAS virulence. Highly encapsulated GAS strains are associated with both invasive infections and outbreaks of acute rheumatic fever. GAS mutants lacking capsule are sensitive to neutrophil killing and have reduced virulence in murine model of GAS infection. In addition to its role in bacterial resistance to host defense attack, HA capsule mediates adherence and promotes GAS colonization of the pharynx. Capsule expression requires effective and sensitive control mechanisms to avoid excessive capsule overproduction. In the current model, CovR binds to the promoter region of the has capsule gene operon comprised of hasABC genes and represses its transcription. However the details of this mechanism are mostly unclear. The primary objective of the proposed research is to understand the molecular mechanisms of HA capsule regulation. In our preliminary studies we identified a novel regulatory noncoding region that controls capsule operon transcription. We confirmed that the region is physiologically significant and is important for full virulence in a mouse model of GAS invasive disease. Moreover, we found that the region is under strong selective pressure resulting in accumulation of spontaneous mutations in GAS clinical strains. We propose to define this novel capsule regulation mechanism using advanced genetic and biochemical techniques. The outcomes of this research are expected to have a positive impact on the development of diagnostic analysis during outbreaks of GAS infection and highly targeted therapeutics to control the invasive GAS disease.