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（由申请方提供）：A组链球菌（GAS）是一种全球重要的人类病原体，可引起咽喉（咽炎）或皮肤（脓疱）的自限性感染，每年导致约7.5亿例感染。由于自身免疫性和侵袭性疾病，GAS与高发病率和死亡率相关。急性风湿热（ARF）是由一种所谓的“致风湿性”菌株引起的GAS咽喉感染治疗不当引起的，并可通过心脏瓣膜的自身免疫攻击导致风湿性心脏病。GAS存在不同的致流变性和非致流变性菌株已被长期认可，但其独特的性质仍然难以捉摸。我们的初步数据显示，从不同疾病（脓疱病>咽炎> ARF）患者中回收的GAS的分泌型半胱氨酸蛋白酶（SpeB）活性存在显著差异。这些发现为一个长期存在的难题提供了一个新的假设：即致风湿性至少部分是与SpeB活性相关（直接或间接）的GAS表型的功能。重要的是，SpeB是细菌细胞转录程序的关键生物标志物，也是一种毒力因子， 通过降解参与防御的人类宿主蛋白质起作用。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SpeB活性差异的分子基础。有待检验的假设是，从不同疾病（ARF和咽炎）中恢复的GAS在转录程序上不同。 这是通过以下方式实现的：通过RNA-Seq（目标1）定义一组选定的GAS生物多样性分离株的转录组，并通过定量RT-PCR和聚类分析（目标2）筛选大量GAS菌株以鉴定区分临床重要亚群的转录特征。该提案为细菌群体水平上的比较转录组学提供了广泛的方法。长期目标是了解不同GAS疾病的分子基础。支持这一假设的数据可能揭示转录途径的改变，这些改变不仅影响speB的表达，还影响可能在触发ARF中起直接作用的其他基因的转录。SpeB活性（或其缺乏）可能通过（缺乏）宿主和/或GAS胞外蛋白的调节直接导致ARF发病机制。总的来说，这项探索性研究可能会导致更全面的未来研究，促进我们对触发ARF的分子过程的理解，改善ARF的实验模型，并更好地为疫苗设计和诊断提供信息。