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：
8962457
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/8962457
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 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 public health relevance 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（由申请人提供）：铜绿假单胞菌是引起微生物性角膜炎的最常见原因之一，在美国和世界范围内，铜绿假单胞菌使用称为 III 型分泌系统的分子注射器来避免被浸润的中性粒细胞杀死，从而避免死亡。根据这些菌株使用其类型注射的效应蛋白，铜绿假单胞菌分离株可分为两类。 III 分泌系统。“细胞毒性”分离株产生 ExoU 和 ExoT，而“侵入性”分离株则产生 ExoS 和 ExoT。我们最近发现铜绿假单胞菌的侵入性分离株利用 ExoS 和 ExoT 来抑制中性粒细胞、活性氧的两种主要杀菌功能。因此，拟议的研究计划将研究抗菌颗粒与含有细菌的吞噬体的融合。 ExoS 和 ExoT 抑制中性粒细胞中的分子途径，以阻止活性氧产生（目标 1）和颗粒融合（目标 2）。我们还将确定将 ExoS- 和 ExoT 注射到中性粒细胞中是否可以在群体水平上促进角膜感染。通过诱导细胞凋亡或效应介导的吞噬作用抑制来灭活中性粒细胞，其中第一个被吞噬的细菌将充当。因此，我们的研究计划旨在发现铜绿假单胞菌抑制的多种细胞过程，并发现治疗干预感染的新方法。。