Tissue-Specific Infection by Group A Streptococci

A 组链球菌的组织特异性感染

• 批准号: 7872639
• 负责人: Debra E BESSEN
• 金额: $ 39.48万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872639
• 关键词: Address; Adherence; Affect; Alleles; Biological; Carrier State; Defect; Disease; Epithelial; Epithelial Cells; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genome; Genotype; Geographic Distribution; Goals; Human; Impetigo; Infection; Knowledge; Mediating; Molecular; Morbidity - disease rate; Organism; Pathway interactions; Pharyngeal structure; Pharyngitis; Pilum; Population; Principal Investigator; Process; Production; Prophylactic treatment; Proteins; Regulation; Regulon; Rheumatic Heart Disease; Role; Site; Skin; Streptococcus pyogenes; Surface; Testing; Tissues; Toxic Shock Syndrome; Viral Tumor Antigens; Virulence; abstracting; mortality; pilus genes; preference; programs; response; sialosyl-T antigen; transmission process

Project Summary/Abstract. Group A streptococci (GAS; Streptococcus pyogenes) are remarkable for the wide range of diseases they cause in humans, their sole biological host. Yet, most infections are mild and involve one of two tissues - the epithelial surface of the throat or skin - giving rise to pharyngitis or impetigo, respectively. A long-term goal is to better understand the distinct pathogenic mechanisms leading to pharyngitis and impetigo. A primary focus of the proposal is the regulation of pili expression in GAS. Pilus-associated proteins mediate adherence to epithelial cells and enhance superficial infection at the skin. Pili correspond to the T-antigens of GAS. All strains examined have pilus genes, however, many natural GAS isolates lack T-antigen. The hypothesis to be tested in Aim 1 states that organisms recovered from a carrier state and/or invasive disease are significantly more likely to have defects in pilus production, as compared to isolates derived from cases of pharyngitis or impetigo. Aim 1 seeks to define the relationship between defects in pilus expression and disease. The nra/rofA locus encodes a ¿stand alone¿ response regulator that affects the transcription of pilus genes; nra and rofA denote discrete lineages of alleles. Both Nra and RofA can have positive or negative regulatory effects on pilus gene transcription, depending on the GAS isolate or strain. The hypothesis to be tested in Aim 2 states that there are strain-specific differences among modulators of pilus gene expression that lie in a pathway upstream of Nra/RofA. Aim 2 seeks to identify regulators of pilus gene transcription having a differential presence among strains. The distribution of Nra and RofA among GAS is strongly correlated with subpopulations of strains having a tendency to cause infection at either the throat or skin. Nra and RofA are global regulators of GAS gene transcription. Two hypotheses will be addressed in Aim 3: (i), that co-regulated non-pilus genes act in concert with pili to cause disease; and (ii), that Nra and RofA confer differential transcription of downstream genes. Aim 3 seeks to identify genes of the Nra and RofA regulons, and to test their role in virulence. Through a better understanding of the molecular mechanisms used by GAS to persist in their primary ecological niches - the throat and skin of the human host - will come new knowledge on how best to interfere with these vital processes. Effective control and prevention measures that disrupt the chain of transmission of GAS will result in a decreased burden of the more severe GAS diseases (toxic shock syndrome, rheumatic heart disease) which have a high morbidity and mortality for many people throughout the world.

项目摘要/摘要。 A 组链球菌（GAS；化脓性链球菌）因其可治疗的多种疾病而著称。 原因是人类是它们唯一的生物宿主。然而，大多数感染都是轻微的，并且涉及两种组织之一： 喉咙或皮肤的上皮表面 - 分别引起咽炎或脓疱病。一个长期目标是 更好地了解导致咽炎和脓疱疮的不同致病机制。主要关注点是 该提案是GAS中菌毛表达的调节。 菌毛相关蛋白介导对上皮细胞的粘附并增强皮肤的浅表感染。 菌毛对应于 GAS 的 T 抗原。所有检查的菌株都具有菌毛基因，然而，许多天然 GAS 分离株缺乏T抗原。目标 1 中要检验的假设表明，从载体中回收的生物体 与相比，状态和/或侵袭性疾病在菌毛产生方面更有可能出现缺陷 源自咽炎或脓疱疮病例的分离株。目标 1 试图定义缺陷之间的关系 菌毛表达和疾病。 nra/rofA 基因座编码一个“独立”反应调节器，影响 菌毛基因的转录； nra 和 rofA 表示等位基因的离散谱系。 Nra 和 RofA 都可以有 对菌毛基因转录的正向或负向调节作用，取决于 GAS 分离株或菌株。这 目标 2 中待检验的假设表明，菌毛调节剂之间存在菌株特异性差异 位于 Nra/RofA 上游途径的基因表达。目标 2 寻求识别菌毛基因的调节因子 转录在菌株之间存在差异。 Nra 和 RofA 在 GAS 中的分布为 与容易引起咽喉或咽部感染的菌株亚群密切相关 皮肤。 Nra 和 RofA 是 GAS 基因转录的全局调节因子。 Aim 将讨论两个假设 3：(i)，共同调控的非菌毛基因与菌毛协同作用导致疾病； (ii) Nra 和 RofA 赋予下游基因的差异转录。目标 3 寻求鉴定 Nra 和 RofA 的基因 调节子，并测试它们的毒力作用。 通过更好地了解 GAS 用来维持其主要功能的分子机制 生态位——人类宿主的喉咙和皮肤——将带来关于如何最好地干预的新知识 与这些重要的过程。采取有效的控制和预防措施，阻断传播链 GAS 将减轻更严重的 GAS 疾病（中毒性休克综合征、风湿病）的负担 心脏病）对全世界许多人来说发病率和死亡率都很高。