Impact of Heme During Group A Streptococcus Infection

项目摘要 这个合作项目的首要目标是定义血红素在细胞中的作用。 A组链球菌（GAS）的病理生理学，旨在开发新的治疗方法 方式。在人类宿主中，血红素有两种作用：既是关键的营养物质，又是有害物质。 因此，对于β-溶血性GAS，血红素管理需要微妙的平衡行为。我们 假设GAS仔细监测细胞外和细胞外血红素的水平， 细胞内区室，并因此部署血红素摄取和使用或解毒， 修复路径。此外，我们提出GAS使用血红素敏感调节蛋白来 影响铁稳态和毒力基因的表达。在本申请中，两个 经验丰富的GAS研究人员（MPI Eichenbaum和McIver）将联合收割机结合分子遗传学和 生物化学方法与转录组研究和全基因组诱变筛选， 确定和表征血红素管理的GAS机制，并确定它们在GAS中的作用 发病机制;我们描述了关键血红素摄取途径和GAS病理生理学（目的1）; 表征促进GAS包膜中血红素抗性的机制（目标2）;以及 分析根据环境因素协调GAS适应的监管框架 血红素（Aim 3）。该项目将有助于揭示血红素在生物体内的根本影响， 人类主要病原体的病理生理学

Project Summary The overarching goal of this collaborative project is to define the role of heme in the pathophysiology of the Group A Streptococcus (GAS) with the aim of developing new treatment modalities. In the human host, heme has two roles: both a critical nutrient and a noxious agent. Thus, for the β-hemolytic GAS, heme management requires a delicate balancing act. We hypothesize that GAS carefully monitors the levels of heme in both the extracellular and intracellular compartments and accordingly deploys heme uptake and use or detoxification and repair pathways. Furthermore, we propose that GAS uses heme-sensitive regulatory proteins to influence the expression of both iron-homeostasis and virulence genes. In this application, two experienced GAS researchers (MPIs Eichenbaum and McIver) will combine molecular genetic and biochemical methods with transcriptome studies and genome-wide mutagenesis screens to identify and characterize GAS mechanisms for heme management and establish their role in GAS pathogenesis; We describe key heme uptake pathways and GAS pathophysiology (Aim 1); characterize the mechanisms that facilitate heme resistance in the GAS envelope (Aim 2); and analyze the regulatory framework that orchestrates GAS adaptation according to environmental heme (Aim 3). This project will help reveal the fundamental impact of heme in the pathophysiology of a major human pathogen.