P. aeruginosa type III secreted effectors in corneal disease

角膜疾病中铜绿假单胞菌 III 型分泌效应子

基本信息

批准号：
9115162
负责人：
Arne Rietsch
金额：
$ 39.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115162
关键词：
1-Phosphatidylinositol 3-Kinase ADP Ribose Transferases ADP ribosylation Anti-Bacterial Agents Apoptosis Bacteria Blindness C-terminal Calcium Categories Cell physiology Cells Clinical Confocal Microscopy Contact Lenses Cornea Corneal Diseases Corneal Stroma Corneal Ulcer Cytoplasmic Granules Data Development Enzymes Exotoxins Eye Infections Funding Grant Health Human Immune Immune system Induction of Apoptosis Infection Infection prevention Inhibition of Apoptosis Injection of therapeutic agent Invaded Keratitis Lead Left Link Mediating Molecular Monitor N-terminal NADPH Oxidase Neutrophil Infiltration Organism Outcome Oxygen Pathogenesis Pathway interactions Phagocytosis Phagocytosis Inhibition Phagosomes Population Production Proteins Pseudomonas Pseudomonas aeruginosa Reactive Oxygen Species Reporting Research Resolution Respiratory Burst Role Signal Pathway Syringes System Testing Therapeutic Type III Secretion System Pathway Virulence Work antimicrobial antimicrobial peptide bactericide base cell type combat corneal epithelium cytotoxic design in vivo killings melting microbial neutrophil novel novel strategies prevent programs research study response rho targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): P. aeruginosa is one of the most common causes of microbial keratitis, both in the U.S. and worldwide. P. aeruginosa uses a molecular syringe, called type III secretion system, to avoid killing by infiltrating neutrophils, thereby preventing clearance of the infection. P. aeruginosa isolates can be divided into two categories, based on the effector proteins these strains inject using their type III secretion system. "Cytotoxic" isolaes produce ExoU and ExoT, whereas "invasive" isolates produce ExoS and ExoT. We recently discovered that invasive isolates of P. aeruginosa use ExoS and ExoT to inhibit the two major bactericidal functions of neutrophils, reactive oxygen species production and fusion of antimicrobial granules with the bacteria-containing phagosome. Accordingly, the proposed program of research will examine the molecular pathways in neutrophils that ExoS and ExoT inhibit to block reactive oxygen species production (Aim 1) and granule fusion (Aim 2). We will also determine whether injection of ExoS- and ExoT into neutrophils can promote corneal infection on a population level, by inactivating neutrophils through induction of apoptosis, or effector-mediated inhibition of phagocytosis. Here the first phagocytosed bacterium would act as a poison pill, inactivating the neutrophil, thereby allowing the other bacteria to thrive (Aim 3). Our program of research is therefore poised to discover multiple cellular processes that are inhibited by P. aeruginosa, and uncover new approaches to therapeutically intervene in the infection.

描述（由适用提供）：铜绿假单胞菌是在美国和全球范围内最常见的微生物角膜炎原因之一。铜绿假单胞菌使用称为III型分泌系统的分子注射器，以避免通过浸润中性粒细胞杀死，从而防止感染清除。铜绿假单胞菌分离株可以根据效应蛋白使用其III型分泌系统注入两类。 “细胞毒性”的分离菌产生了外观和外观，而“入侵”分离株产生了exos和Exot。我们最近发现，铜绿假单胞菌的侵入性分离株使用外ex和Exot抑制中性粒细胞的两个主要细菌功能，活性氧的产生以及抗菌颗粒与含细菌的吞噬体的融合。彼此之间，拟议的研究计划将检查中性粒细胞中的分子途径，这些嗜中性粒细胞抑制了抑制可阻止活性氧的产生（AIM 1）和颗粒融合（AIM 2）。我们还将通过通过诱导凋亡诱导中性粒细胞或效应子介导的抑制吞噬作用来确定将外虫和外孔注射到中性粒细胞中可以在人群水平上促进中心感染。在这里，第一个吞噬细胞的细菌将充当毒药，使中性粒细胞失活，从而使其他细菌繁殖（AIM 3）。因此，我们的研究计划被毒死，以发现铜绿假单胞菌抑制的多种细胞过程，并发现了治疗方法干预感染的新方法。