Molecular mechanism of virulence regulation in Streptococcus pyogenes

化脓性链球菌毒力调控的分子机制

• 批准号: 9206980
• 负责人: Muthiah Kumaraswami
• 金额: $ 39.88万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206980
• 关键词: Acute Rheumatic Heart Disease; Amino Acid Sequence; Amino Acids; Anatomy; Animal Model; Animals; Architecture; Bacterial Toxins; Biochemical; Biophysics; Caspase; Cell Density; Cessation of life; Clinical; Cues; DNA Sequence; Data; Dependence; Development; Disease; Disease Outbreaks; Ectopic Expression; Foundations; Gene Expression; Gene Expression Regulation; Generations; Genetic; Genetic Transcription; Genome; Goals; Growth; Human; Impetigo; Infection; Knowledge; Lead; Life; Ligands; Measures; Mediating; Membrane; Methods; Modeling; Molecular; Molecular Target; Necrotizing fasciitis; Oligopeptides; Orthologous Gene; Pathogenesis; Pathogenicity; Peptide Biosynthesis; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Peptidylprolyl Isomerase; Pharyngeal structure; Pharyngitis; Phase; Phenotype; Population Density; Production; Proteins; Proteolytic Processing; Publishing; Regulation; Regulator Genes; Regulatory Pathway; Research; Role; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sodium Chloride; Specificity; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Testing; Toxic Shock Syndrome; Transcriptional Regulation; Virulence; Virulence Factors; Work; antimicrobial; biophysical techniques; burden of illness; erythrogenic toxin; interdisciplinary approach; mutant; novel; novel therapeutics; pathogen; permease; prophylactic; public health relevance; response; signal peptidase; therapeutic target

 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.

 描述（由申请人提供）：A组链球菌（GAS）是一种独特的人类病原体，可引起广泛的疾病。由GAS感染引起的疾病负担是显著的，因为仅侵袭性GAS感染每年就造成全球约50万人死亡。鉴于入侵性感染的治疗困难、GA入侵性疾病暴发的增加以及缺乏有效的预防措施，研究其毒力调控机制并确定新的抗菌靶标至关重要。分泌型半胱氨酸蛋白酶SpeB在感染过程中大量产生，对GAS侵袭性感染的发病机制至关重要。GAS全局转录调节因子RopB以生长期依赖性方式控制约25%的GAS基因组（包括speB）的表达。虽然RopB是转录调控所必需的，但它需要生长期特异性输入信号来介导基因调控。使用多学科的方法，我们最近证明，RopB使用气体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。我们的研究表明，肽信号来源于分泌信号序列的Vfr抑制RopB依赖的毒力基因的表达在低细胞密度。尽管我们的初步数据表明高细胞密度特异性激活肽信号激活RopB介导的基因调控，但肽信号的遗传和生物化学身份仍然未知。使用遗传学，生物化学，生物物理学方法和感染的动物模型相结合，我们将研究这个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。从这项研究中产生的数据将阐明一个重要的毒力调控途径的关键组成部分，并可能阐明新的分子靶点，用于开发治疗GAS侵袭性感染的抗菌药物。