Heme Acquisition in Group A Streptococcus

描述(申请人提供)：溶血性化脓性链球菌，俗称A组链球菌(GAS)，是一种重要的人类病原体，可引起咽炎、蜂窝织炎、猩红热、坏死性筋膜炎、中毒性休克综合征、急性风湿热、风湿性心脏病和肾小球肾炎。GAS感染的发病机制是由大量毒力因子介导的，这使得GAS疾病的有效免疫治疗控制变得极其困难。许多细菌病原体的铁摄取系统是致病的关键因素。它们在毒力、保守的抗原性和表面暴露方面的作用使它们成为有吸引力的候选疫苗。GAS可以从血红蛋白中隔离铁，而血红素被认为是体内GAS的主要铁源。然而，人们对气体中获取血红素的机制知之甚少。最近，我们发现了一种新的血红素相关细胞表面蛋白(简称SHP1)，它是由GAS合成的。Shp 1基因与8个相邻的下游基因，包括spy1795、spy1794和spy1793共转录，编码与革兰氏阴性细菌铁摄取相关的ABC转运蛋白成分的同源基因。我的初步结果表明，气体转运蛋白的脂蛋白成分(Spy1795，命名为Shp2)也与血红素结合。拟议的研究将调查sht基因座(包括shp1和shp2)是否编码了气体中获取血红素的机制，以及是否需要sht来维持气体的毒力。我计划实现以下具体目标，使用生化和遗传方法以及感染模型来确定血红素获取在GAS发病机制中的作用。 目的1.确定重组Shp2是否与血红素结合 目的2.阐明sht基因座是否编码了获取血红素的转运蛋白系统 目的3.研究SHP1和/或Shp2的破坏是否减弱毒力 这项研究将促进我们对GAS中血红素获得机制的理解，并可能发现新的潜在GAS候选疫苗(S)。

DESCRIPTION (provided by applicant): Hemolytic Streptococcus pyogenes, commonly referred as Group A Streptococcus (GAS), is an important human pathogen causing pharyngitis, cellulitis, scarlet fever, necrotizing fasciitis, toxic shock syndrome, acute rheumatic fever, rheumatic heart disease, and glomerulonephritis. The pathogenesis of GAS infection is mediated by an abundance of virulence factors which make effective immunotherapeutic control of GAS diseases extremely difficult. Iron acquisition systems of many bacterial pathogens are key virulence factors. Their role in virulence, conserved antigenicity, and surface exposure make them attractive vaccine candidates. GAS can sequester iron from hemoglobin and heme is thought to be the primary iron source for GAS in vivo. However, little is known about the machinery for heme acquisition in GAS. Recently, we identified a novel heme-associated cell-surface protein (designated Shp1) made by GAS. The shp 1 gene is co-transcribed with 8 contiguous downstream genes, including spy1795, spy1794, and spy1793 encoding homologues of the components of ABC transporters involved in iron uptake in Gramnegative bacteria. My preliminary results suggest that the lipoprotein component (Spy1795, designated Shp2) of the GAS putative transporter also binds heme. The proposed studies will investigate whether the sht locus (containing shp1 and shp2) encodes the machinery for heme acquisition in GAS and if sht is required for GAS virulence. I plan to achieve the following specific aims using biochemical and genetic approaches and infection models to define the role of heme acquisition in GAS pathogenesis. Aim 1. Determine whether recombinant Shp2 binds heme Aim 2. Elucidate if the sht locus encodes a transporter system for heme acquisition Aim 3. Investigate whether the disruption of shp1 and/or shp2 attenuates GAS virulence The study will advance our understanding of the mechanism of heme acquisition in GAS and may identify new potential GAS vaccine candidate(s).