Population analysis of group A streptococcal phenotypes

A 组链球菌表型的群体分析

基本信息

批准号：
9196327
负责人：
Debra E BESSEN
金额：
$ 20.3万
依托单位：
NEW YORK MEDICAL COLLEGE
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：
2015-12-16 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196327
关键词：
Acute Acute Pharyngitis Affect Autoimmune Process Basal Ganglia Biological Biological Markers Biology Brain Cardiovascular Diseases Caspase Cells Cessation of life Child Clinical Clinical Management Cluster Analysis Complex Data Development Diagnostic Disease Disease Outbreaks Experimental Models Extracellular Protein Foundations Future Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Genetic Transcription Goals Heart Diseases Heart Valves Human Impetigo Individual Infection Knowledge Lead Molecular Morbidity - disease rate Myocardial Infarction Organism Pathogenesis Pathway interactions Patient Isolators 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 pyogenes Surface Sydenham Chorea Testing Upper Respiratory Infections Upper respiratory tract Vaccine Design Vaccines Virulence Factors comparative epidemiology study improved mortality multiple myeloma M Protein neuropsychiatric disorder novel pathogen programs public health relevance screening transcriptome transcriptome sequencing transcriptomics virtual

项目摘要

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（由适用提供）：A组链球菌（气体）是一种全球重要性的人类病原体，会引起喉咙（咽炎）或皮肤（盗窃）自限制感染，每年导致约7.5亿感染。气体与由于自身免疫性和侵入性疾病引起的高发病率和死亡率有关。急性风湿热（ARF）遵循所谓的“风湿性”菌株一种经过的燃气喉咙感染不足，可以通过心脏瓣膜自身免疫性攻击导致风湿性心脏病。长期以来，人们已经认识到，存在独特的风湿性和非炎症性菌株的存在，但它们的独特特性仍然难以捉摸。我们的初步数据显示，从不同疾病的患者（盗窃>咽炎> ARF）中回收的气体的分泌半胱氨酸蛋白（SPEB）的活性显着差异。这些发现为长期存在的难题提供了新的假设的支持：流变性至少部分是与SPEB活性相关的气体表型的函数。重要的是，SPEB是细菌细胞转录程序的关键生物标志物，也是病毒因子通过降解参与防御的人类宿主蛋白的作用。总体目标是描绘由于转录网络差异而导致的ARF与咽炎相关气体中差异性SPEB活性的分子基础。要检验的假设是，从不同疾病（ARF和咽炎）中回收的气体在其转录程序中有所不同。通过定义通过RNA-Seq（AIM 1）定义一组精选的生物学上不同气体分离株的转录组，并筛选大量的气体菌株，以通过定量的RT-PCR和CLUSTER分析（AIM 2）筛选大量的气体菌株。该提案为细菌种群水平上的比较转录组学提供了广泛的方法。一个长期目标是了解不同气体疾病的分子基础。支持假设的数据可能会发现不仅影响SPEB表达的转录途径的变化，而且还影响了可能在触发ARF中具有直接作用的其他基因的转录。 SPEB活性（或其不存在）可能直接通过（缺乏）宿主和/或气体外细胞外蛋白的调节来导致ARF发病机理。总体而言，这项探索性研究可能会导致更全面的未来研究，以提高我们对触发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。