Molecular mechanism of virulence regulation in Streptococcus pyogenes

化脓性链球菌毒力调控的分子机制

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：A组链球菌（气）是一种独家人类病原体，可引起各种各样的疾病。由于燃气感染引起的疾病燃烧非常重要，因为仅侵入性气体感染每年在全球范围内约500,000人死亡。鉴于难以治疗侵入性感染，GA侵入性疾病暴发的升高以及缺乏有效的预防性措施，研究病毒调节机制并鉴定新的抗菌靶标至关重要。分泌的半胱氨酸蛋白SPEB在感染过程中彻底产生，对于气体浸润性感染的发病机理至关重要。气体全球转录调节剂ROPB以生长期依赖性方式控制了〜25％的气体基因组的表达。尽管ROPB对于转录调节至关重要，但它需要生长相特定的输入信号来介导基因调节。使用多学科方法，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与细胞密度的病毒调节。我们的研究表明，源自VFR的分泌信号序列的肽信号在低细胞密度期间抑制ROPB依赖性病毒基因表达。尽管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介导的基因调节，但肽信号的遗传和生化身份均未清楚。使用遗传，生化，生物物理方法和感染动物模型的组合，我们将研究该信号传导电路的三个主要方面，即信号产生，信号灵敏度和信号传递。从这项研究产生的数据将阐明重要的毒力调节途径的关键成分，并可能阐明新型分子靶标，以开发抗菌剂以治疗气体侵入性感染。