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Impact of Heme During Group A Streptococcus Infection

A 族链球菌感染期间血红素的影响

基本信息

批准号：
10825476
负责人：
ZEHAVA EICHENBAUM
金额：
$ 64.72万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10825476
关键词：
Acute Disease Antibodies Area Binding Biochemical Cell Wall Complement Complex Cues Development Dimensions Disease Drug Metabolic Detoxication Elements Functional disorder Gene Expression Genes Goals Group Processes Growth Heme Heme Iron Hemeproteins Hemostatic function Homeostasis Human Human body Hypersensitivity Individual Infection Inflammation Injury Intervention Iron Mediator Membrane Lipids Membrane Proteins Metabolism Metals Methods Modality Molecular Molecular Genetics Monitor Muramidase Mutagenesis Nature Nutrient Nutritional Nutritional Immunity Operon Pathogenesis Pathway interactions Phosphotransferases Play Prevention Property Proteins Reactive Oxygen Species Regulatory Pathway Research Personnel Resistance Role Shapes Signal Transduction Source Streptococcal Infections Streptococcus pyogenes Stress System Testing Toxic effect Virulence Virulence Factors cell envelope cell injury differential expression experience extracellular fitness genetic regulatory protein genome-wide heme a heme receptor holistic approach human pathogen in vivo insight lipophilicity novel novel strategies pathogen repaired response sensor success transcriptome transposon sequencing uptake vaccine access virulence gene

项目摘要

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.

项目总结