Regulation of hyaluronic acid capsule biosynthesis in Streptococcus pyogenes

描述（由申请人提供）： 化脓性链球菌（Streptococcus pyogenes，GAS）是一种重要的人类病原体，其引起许多疾病，从轻微的皮肤和咽喉感染如脓疱病和咽炎到危及生命的侵入性感染如链球菌中毒综合征和坏死性筋膜炎。全球GAS感染每年造成超过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GAS疾病在全球范围内有所增加。虽然病原体对抗生素治疗敏感，但严重的侵袭性GAS感染通常难以治疗。透明质酸（HA）被认为是GAS毒力的主要决定因素之一。高度包裹的GAS菌株与侵袭性感染和急性风湿热的爆发有关。缺乏包膜的GAS突变体对嗜中性粒细胞杀伤敏感，并且在GAS感染的小鼠模型中具有降低的毒力。除了在细菌耐药性中的作用外， 对于宿主防御攻击，HA胶囊介导粘附并促进咽部的GAS定殖。胶囊表达需要有效和敏感的控制机制，以避免过度的胶囊生产过剩。在目前的模型中，CovR结合到由hasABC基因组成的has胶囊基因操纵子的启动子区域并抑制其转录。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胶囊调控的分子机制。在我们的初步研究中，我们确定了一个新的调控非编码区，控制胶囊操纵子转录。我们证实了该区域具有生理学意义，并且对于GAS侵袭性疾病小鼠模型中的完全毒力非常重要。此外，我们发现该区域处于强选择压力下，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。这项研究的结果预计将对GAS感染爆发期间的诊断分析和控制侵袭性GAS疾病的高度靶向治疗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.