Tissue-Specific Infection by Group A Streptococci

项目概要/摘要。 A组链球菌（GAS;化脓性链球菌）因其广泛的疾病而引人注目， 因为人类是它们唯一的生物宿主。然而，大多数感染是温和的，涉及两种组织之一- 咽喉或皮肤的上皮表面-分别引起咽炎或脓疱。长期目标是 更好地了解导致咽炎和脓疱的不同致病机制。的主要焦点 该建议是GAS中皮利表达的调节。 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。 皮利对应于GAS的T抗原。所有检测的菌株都有菌毛基因，然而，许多天然GAS 分离物缺乏T抗原。目标1中有待检验的假设指出，从载体中回收的微生物 状态和/或侵入性疾病更可能具有菌毛产生缺陷， 分离自咽炎或脓疱病病例。目标1旨在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反应调节因子， 菌毛基因的转录; nra和rofA表示等位基因的离散谱系。NRA和RofA都可以拥有 对菌毛基因转录的正或负调节作用，取决于GAS分离株或菌株。的 目标2中待检验的假设指出，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。目的2旨在鉴定菌毛基因的调节因子 在不同的菌株之间有差异的转录。Nra和RofA在GAS中的分布为： 与倾向于在咽喉或咽喉部引起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。两个假设将在Aim中讨论 3：（i），共调节的非菌毛基因与皮利协同作用引起疾病;和（ii），Nra和RofA 赋予下游基因的差异转录。目的3旨在确定Nra和RofA的基因 调节子，并测试其在毒性中的作用。 通过更好地理解GAS用于坚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。 这些重要的过程。有效的控制和预防措施， GAS将导致更严重的GAS疾病（中毒性休克综合征、风湿性关节炎、呼吸道感染）的负担降低。 心脏病），其对于全世界许多人具有高发病率和死亡率。

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.