Type III Secretion Translocon Structure and Function

III型分泌易位子的结构和功能

基本信息

批准号：
8701601
负责人：
Arne Rietsch
金额：
$ 23.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701601
关键词：
Aeromonas hydrophila Antibiotic Resistance Bacteremia Bacteria Biological Assay Burn injury Bypass Cell membrane Cells Corneal Injury Cysteine Cytoplasm Data Development Disease Docking Drug Targeting Engineering Erythrocyte Membrane Genetic Genetic Techniques Heart Hospitals Immune system In Vitro Infection Injection of therapeutic agent Maps Membrane Molecular Mutation Nature Needles Nosocomial Infections Pasteurella pseudotuberculosis Patients Pneumonia Process Protein-Protein Interaction Map Proteins Pseudomonas aeruginosa Resistance Severity of illness Structure Surface Syringes Techniques Testing Therapeutic Intervention Type III Secretion System Pathway Ventilator Virulence Factors Work antimicrobial crosslink design disulfide bond drug development efflux pump hybrid protein in vivo interest loss of function mortality mutant neutrophil pathogen prevent public health relevance research study resistance mechanism success

项目摘要

DESCRIPTION (provided by applicant): P. aeruginosa is a common cause of hospital-acquired infections. It uses a type III secretion system to directly inject effector proteins into targeted host cells, in particular neutrophils, thereby preventing clearance by the host immune system. Injection of effector proteins involves a specialized structure called the translocon, which consists of a pore in the host cell membrane that interacts with the tip of the type III secretion needle. While the translocon is critical for type III secretion function, it has been difficult to study biochemically. Here we propose to use a genetic technique to identify critical translocator interactions and categorize them according to their function in the translocation process (translocator insertion, pore formation, docking of the tip to the pore and triggering of effector secretion). Identifying translocator contacts that are critical for function not only increases our understanding of the translocon, it also identifies potential targets for therapeutic intervention that lie outside of the bacterial cell and are therefore not shielded by conventional antibiotic resistance mechanisms, such as the outer membrane or efflux pumps.

描述（由申请人提供）：铜绿假单胞菌是医院获得感染的常见原因。它使用III型分泌系统将效应蛋白直接注入靶向宿主细胞，尤其是中性粒细胞，从而防止宿主免疫系统清除。注入效应蛋白涉及一种称为The Clansocon的专业结构，该结构由宿主细胞膜中的孔组成，该结构与III型分泌针头相互作用。虽然易位对于III型分泌功能至关重要，但在生化上很难研究。在这里，我们建议使用一种遗传技术来识别关键的转运剂相互作用，并根据其在易位过程中的功能（转运器插入，孔形成，尖端对接到孔隙到孔的孔隙和触发器分泌的触发）。识别对功能至关重要的转运剂的接触，不仅可以增加我们对转运的理解，还可以确定治疗的潜在靶标位于细菌细胞外的干预措施，因此不受常规的抗生素耐药性机制（例如外膜或外膜泵）的掩护。