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（气体链球菌为链球菌）对于多种疾病而言是显着的 在人类中，他们的唯一生物宿主。然而，大多数感染是温和的，涉及两次 - 喉咙或皮肤的上皮表面 - 分别引起咽炎或盗窃。一个长期目标是 更好地了解导致咽炎和盗窃的独特致病机制。主要重点 该提议是对气体中菌毛表达的调节。 菌毛相关的蛋白质介导对上皮细胞的粘附并增强皮肤的表面感染。 pili对应于气体的T抗原。但是，所有检查的菌株均具有活塞基因，但是许多天然气 分离物缺乏T抗原。在AIM 1中要检验的假设，即从载体中回收的生物 与状态和/或侵入性疾病相比 源自咽炎或盗窃病例的分离株。 AIM 1试图定义缺陷之间的关系 在菌毛表达和疾病中。 NRA/ROFA基因座编码一个独立的响应调节器，影响了 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 取决于气体分离物或应变，对Pyrus基因转录的阳性或负调控作用。这 在AIM 2状态下要检验的假设，即Pyrus调节剂之间存在菌株特异性差异 基因表达位于NRA/ROFA上游的途径中。 AIM 2试图识别Pyrus基因的调节剂 转录在菌株之间具有差异的存在。 NRA和ROFA在天然气中的分布是 与在喉咙或在喉咙或 皮肤。 NRA和ROFA是气体基因转录的全球调节剂。 AIM将解决两个假设 3：（i），该共同调节的非幼儿基因与PILI一起起作用，以引起疾病； （ii），那个NRA和ROFA 下游基因的会议差分转录。 AIM 3试图识别NRA和ROFA的基因 调节，并测试其在病毒中的作用。 通过更好地理解气体在其主要中持续存在的分子机制 生态壁ni-人类宿主的喉咙和皮肤 - 将获得有关如何最好地干预的新知识 在这些重要过程中。有效的控制和预防措施破坏了 气体将导致更严重的气体疾病燃烧（毒性休克综合征，风湿性） 心脏病）对世界上许多人的发病率和死亡率很高。