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 A组链球菌(GAS)的病理生理学及开发新治疗方法 医疗模式。在人类宿主中，血红素有两个角色：既是关键的营养物质，也是有毒的媒介。 因此，对于β-溶血气体，血红素的管理需要微妙的平衡行动。我们 假设GAS仔细监测细胞外和细胞内的血红素水平 细胞内隔间，并相应地部署血红素的摄取和使用或解毒和 修复小路。此外，我们认为GAS使用对血红素敏感的调节蛋白来 影响铁稳态和毒力基因的表达。在此应用程序中，有两个 经验丰富的气体研究人员(MPI Eichenbaum和McIver)将结合分子遗传学和 转录组研究和全基因组突变筛选的生化方法 确定和描述用于管理血红素的气体机制，并确定它们在气体气体中的作用 发病机制：我们描述了主要的血红素吸收途径和GAS病理生理学(目标1)； 描述在气体包膜中促进血红素抵抗的机制(目标2)；以及 根据环境分析协调气体适应的监管框架 亚铁血红素(目标3)。这个项目将有助于揭示血红素对人类健康的根本影响。 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.