C-di-AMP signaling in S. aureus

金黄色葡萄球菌中的 C-di-AMP 信号传导

基本信息

批准号：
10552662
负责人：
Joshua Woodward
金额：
$ 54.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552662
关键词：
Adolescent Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Bacteria Bacterial Infections Bacterial Physiology Binding Biochemical Cells Cessation of life Chronic Cladribine Clinical Cystic Fibrosis Disease Disease Progression Enzymes Exhibits Gene Expression Regulation Growth Human Genetics Immune System Diseases Immunity Infection Infectious Skin Diseases Inflammation Inflammatory Influenza Interferon-beta Interferons Laboratories Link Longitudinal cohort Lung infections Mediating Mediator Metabolism Modeling Molecular Monitor Morbidity - disease rate Multi-Drug Resistance Mus Nucleotides Organism Outcome Pathogenesis Pathologic Pathology Periodicity Phenotype Physiology Pneumonia Predisposition Process Production Proteins Proteobacteria Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Role Second Messenger Systems Signal Transduction Signaling Molecule Skin Tissue Soft Tissue Infections Staphylococcus aureus Staphylococcus aureus infection Study models Testing Therapeutic Intervention Thymidine Tissues Variant Virulence Wound Infection acute infection cell behavior chronic infection chronic wound co-infection cystic fibrosis patients environmental change genetic association human disease human morbidity human mortality immune activation in vivo insight mortality new therapeutic target novel pulmonary function decline receptor response soft tissue superinfection thymidylate kinase tissue culture

项目摘要

Abstract Staphylococcus aureus is a leading cause of human morbidity and mortality, causing infection of the skin and soft tissues, post-surgical wounds, and lung infection among influenza and cystic fibrosis patients. Widespread multi-drug resistance has made eradication of S. aureus increasingly challenging, necessitating a deeper understanding of the physiology and pathogenesis associated with these organisms. A key aspect of bacterial survival and adaptation to altered environmental conditions is the ability to rapidly alter cellular behavior through second messenger signal transduction. C-di-AMP has recently emerged as a key regulator of bacterial physiology, pathogenesis, and immune activation. In the context of S. aureus, we believe that c- di-AMP produced by S. aureus has three important roles; (i) as a signaling molecule that mediates S. aureus metabolism and antibiotic resistance, (ii) as a bacterial PAMP that promotes pathological inflammation and host susceptibility to bacterial infection, and (iii) as a mediator of inter-bacterial signaling that alters the outcome of co-infections. Findings from these studies may have significant impacts on the course of antibiotic therapy during S. aureus infection and may uncover a novel target to eradicate recalcitrant S. aureus and the inflammation itpromotes.

抽象的金黄色葡萄球菌是人类发病率和死亡率的主要原因，导致感染皮肤和软组织，手术后伤口以及流感和囊性的肺部感染纤维化患者。广泛的多药耐药性已经消除了金黄色葡萄球菌越来越具有挑战性，需要更深入地了解生理学和与这些生物有关的发病机理。细菌生存和适应的关键方面改变环境条件是能够通过第二次快速改变细胞行为的能力 Messenger信号转导。 C-DI-AMP最近成为细菌的关键调节剂生理，发病机理和免疫激活。在金黄色葡萄球菌的背景下，我们相信金黄色葡萄球菌生产的DI-AMP具有三个重要角色。（i）作为介导的信号分子金黄色葡萄球菌的代谢和抗生素耐药性，（ii）作为促进的细菌症状病理炎症和宿主对细菌感染的敏感性，（iii）作为介体细菌间信号传导改变了共同感染的结果。这些研究的发现可能在金黄色葡萄球菌感染期间对抗生素疗法产生重大影响，可能发现一个新的靶标，可以消除顽固的金黄色葡萄球菌和炎症ITPROMOTES。