Molecular mechanism of virulence regulation in Streptococcus pyogenes

 描述(由申请人提供)：A组链球菌(GAS)是一种独有的人类病原体，可导致多种疾病。气体感染造成的疾病负担很大，因为仅侵入性气体感染每年就导致全球约50万人死亡。鉴于治疗侵袭性感染的困难，GA侵袭性疾病暴发的增加，以及缺乏有效的预防措施，研究毒力调节机制和寻找新的抗微生物靶点至关重要。分泌型半胱氨酸蛋白酶SpeB在感染过程中大量产生，在GAS侵袭性感染的发病机制中起关键作用。GAS全局转录调节因子RopB以生长阶段依赖的方式控制包括SpeB在内的~25%的GAS基因组的表达。虽然RopB在转录调控中是必不可少的，但它需要生长阶段特定的输入信号来介导基因调控。利用多学科的方法，我们最近证明了RopB使用GAS编码的分泌肽作为细胞间信号来控制毒力调节与细胞密度一致。我们的研究表明，来自Vfr分泌信号序列的多肽信号在低细胞密度下抑制依赖于RopB的毒力基因的表达。虽然我们的初步数据表明，高细胞密度特异性激活肽信号(S)激活了ropB介导的基因调控，但这些肽信号的遗传和生化特性尚不清楚。结合遗传、生化、生物物理和动物感染模型，我们将研究这一信号通路的三个主要方面，即信号产生、信号传感和信号转导。这项研究产生的数据将阐明一个重要的毒力调节途径的关键成分，并可能阐明开发抗微生物药物治疗气体侵袭性感染的新分子靶点。

 DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) is an exclusive human pathogen that causes a wide spectrum of disease conditions. Disease burden caused by GAS infections is significant as the invasive GAS infections alone account for approximately 500,000 deaths worldwide every year. Given the difficulties in treating the invasive infections, rise in GA invasive disease outbreaks, and lack of effective prophylactic measures, it is critical to investigate the virulence regulatory mechanisms and identify novel antimicrobial targets. Secreted cysteine protease, SpeB, is produced abundantly during infection and is critical for the pathogenesis of GAS invasive infections. GAS global transcription regulator, RopB, controls the expression of ~ 25% of GAS genome including speB in a growth phase- dependent manner. Although RopB is essential for the transcription regulation, it requires growth- phase-specific input signals to mediate gene regulation. Using a multidisciplinary approach, we recently demonstrated that RopB uses GAS-encoded secreted peptides as intercellular signals to control virulence regulation in concert with cell density. Our studies revealed that peptide signals originating from the secretion signal sequence of Vfr inhibits RopB-dependent virulence gene expression during low cell density. Although our preliminary data indicate that high cell density- specific activation peptide signal(s) activates RopB-mediated gene regulation, both the genetic and biochemical identity of the peptide signals remain unknown. Using a combination of genetic, biochemical, biophysical approach, and animal models of infection, we will study three major aspects of this signaling circuit namely, signal generation, signal sensing, and signal transduction. Data generated from this study will elucidate the key components of an important virulence regulatory pathway and may elucidate novel molecular targets for the development of antimicrobials to treat GAS invasive infections.