Population analysis of group A streptococcal phenotypes

A 组链球菌表型的群体分析

• 批准号: 9035797
• 负责人: Debra E BESSEN
• 金额: $ 25.69万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-16 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035797
• 关键词: Acute; Acute Disease; Acute Pharyngitis; Affect; Autoimmune Process; Basal Ganglia; Biological Markers; Biology; Brain; Cardiovascular Diseases; Caspase; Cells; Cessation of life; Child; Clinical Management; Cluster Analysis; Complex; Data; Development; Diagnostic; Disease; Disease Outbreaks; Epidemiologic Studies; Experimental Models; Extracellular Protein; Foundations; Future; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Heart Diseases; Heart Valves; Human; Impetigo; Individual; Infection; Knowledge; Lead; Molecular; Morbidity - disease rate; Organism; Pathogenesis; Pathway interactions; Patients; Pharyngeal structure; Pharyngitis; Phenotype; Physiological; Population; Population Analysis; Population Group; Prevalence; Process; Property; Proteins; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rheumatic Fever; Rheumatic Heart Disease; Role; Scheme; Serotyping; Skin; Streptococcus; Streptococcus pyogenes; Surface; Sydenham Chorea; Testing; Upper Respiratory Infections; Upper respiratory tract; Vaccine Design; Vaccines; Virulence Factors; base; comparative; improved; mortality; multiple myeloma M Protein; neuropsychiatric disorder; novel; pathogen; programs; screening; transcriptome; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant):Group A Streptococcus (GAS) is a human pathogen of global importance that causes self-limiting infections at the throat (pharyngitis) or skin (impetigo), leading to ~750 million infections per year. GAS is associated with high rates of morbidity and mortality due to autoimmune and invasive disease. Acute rheumatic fever (ARF) follows an inadequately treated GAS throat infection by a so-called "rheumatogenic" strain, and can lead to rheumatic heart disease via autoimmune attack of heart valves. The existence of distinct rheumatogenic and non-rheumatogenic strains of GAS has been long recognized, yet their unique properties remain elusive. Our preliminary data shows significant differences in the activity of a secreted cysteine protease (SpeB) for GAS recovered from patients with different diseases (impetigo > pharyngitis > ARF). These findings provide support for a novel hypothesis for a longstanding puzzle: That rheumatogenicity is, at least in part, a function of a GAS phenotype that is related (directly or indirectly) to SpeB activity. Importantly, SpeB is a key biomarker for the transcriptional program of the bacterial cell, as well as a virulence factor that acts by degrading human host proteins involved in defense. The overall goal is to delineate the molecular basis for differential SpeB activity among ARF- versus pharyngitis-associated GAS due to differences in transcriptional networks. The hypothesis to be tested is that GAS recovered from different diseases - ARF and pharyngitis - differ in their transcriptional programs. This is to be achieved by defining the transcriptomes of a select set of biologically diverse isolates of GAS, via RNA-Seq (Aim 1), and screening a large population of GAS strains in order to identify transcriptional signatures that distinguish clinically important sub-populations, via quantitative RT-PCR and cluster analysis (Aim 2). The proposal provides a broad approach for comparative transcriptomics on a bacterial population level. A long-term goal is to understand the molecular basis for distinct GAS diseases. Data supporting the hypothesis may uncover alterations in transcriptional pathways that affect not only speB expression, but also transcription of other genes which may have a direct role in triggering ARF. SpeB activity (or its absence) may directly contribute to ARF pathogenesis through (lack of) modulation of host and/or GAS extracellular proteins. Overall, this exploratory study may lead to more comprehensive future studies that advance our understanding of the molecular processes triggering ARF, improve experimental models for ARF, and better inform vaccine design and diagnostics.

 描述（由申请人提供）：A 族链球菌 (GAS) 是一种具有全球重要性的人类病原体，可引起咽喉（咽炎）或皮肤（脓疱疮）自限性感染，每年导致约 7.5 亿例与 GAS 相关的感染。由于所谓的 GAS 咽喉感染治疗不当，导致急性风湿热 (ARF) 的发病率和死亡率很高。人们早已认识到 GAS 存在不同的风湿性和非风湿性菌株，但它们的独特特性仍然难以捉摸。从患有不同疾病（脓疱疮 > 咽炎 > ARF）的患者中恢复的 GAS 的分泌型半胱氨酸蛋白酶 (SpeB) 的活性这些发现为新的假设提供了支持。一个长期存在的难题是：风湿性至少部分是与 SpeB 活性（直接或间接）相关的 GAS 表型的功能。重要的是，SpeB 也是细菌细胞转录程序的关键生物标志物。作为毒力因子 总体目标是描绘 ARF 与咽炎相关 GAS 之间由于转录网络差异而导致的 SpeB 活性差异的分子基础。要测试的假设是 GAS 从不同疾病中恢复。 - ARF 和咽炎 - 其转录程序不同。 这是通过 RNA-Seq 定义一组选定的生物多样性 GAS 分离株的转录组来实现的（目标 1），并筛选大量 GAS 菌株，以确定区分临床重要亚群的转录特征，通过定量 RT-PCR 和聚类分析（目标 2），该提案为细菌群体水平的比较转录组学提供了一种广泛的方法，长期目标是了解支持不同 GAS 疾病的分子基础。假设可能揭示转录途径的改变，这些改变不仅影响 speB 表达，而且影响其他基因的转录，这些基因可能在触发 ARF 中发挥直接作用，SpeB 活性（或缺乏）可能通过（缺乏）调节直接促进 ARF 发病机制。总体而言，这项探索性研究可能会带来更全面的未来研究，从而增进我们对触发 ARF 的分子过程的理解，改进 ARF 的实验模型，并更好地为疫苗设计和诊断提供信息。