Tissue-Specific Infection by Group A Streptococci

项目摘要/摘要。 A组链球菌(GAS；化脓性链球菌)以其广泛的疾病范围而引人注目 因为在人类中，它们唯一的生物宿主。然而，大多数感染都是轻微的，涉及两种组织之一-- 咽喉或皮肤上皮表面--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病的不同致病机制。的主要关注点 这项建议是对菌毛在GAS中的表达进行监管。 菌毛相关蛋白介导与上皮细胞的黏附，并加强皮肤表面的感染。 菌毛与GAS的T抗原相对应。所有被检查的菌株都有菌毛基因，然而，许多天然气 分离株缺乏T抗原。将在目标1中测试的假设表明，生物体是从载体中恢复的 国家和/或侵袭性疾病明显更有可能在菌毛生产方面存在缺陷，与 来自咽炎或脓疱病病例的分离株。目标1试图定义缺陷之间的关系 在菌毛表达和疾病上。NRA/rofA基因座编码一个独立的反应调节因子，它影响 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 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。这个 将在AIM 2中测试的假设表明，菌毛的调节器之间存在特定菌株的差异 位于NRA/RofA上游的基因表达。AIM 2试图确定菌毛基因的调控因子 不同品系之间存在差异的转录。NRA和RofA在气体中的分布为 与有可能导致咽喉或喉部感染的菌株亚群密切相关 皮肤。NRA和RofA是GAS基因转录的全球调节因子。在AIM中将提出两个假设 3：(I)共同调控的非菌毛基因与菌毛共同作用致病；以及(Ii)NRA和RofA 授予下游基因的差异转录。AIM 3试图确定NRA和RofA的基因 并测试它们在毒力中的作用。 通过更好地理解气体用于维持其原始状态的分子机制 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 这些至关重要的过程。采取有效的控制和预防措施，扰乱艾滋病的传播链条 气体将导致更严重的气体疾病(中毒性休克综合征，风湿病)的负担减轻 心脏病)，对世界各地的许多人来说，发病率和死亡率都很高。

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.