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

• 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
• 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

 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(申请人提供)：在美国和全世界，铜绿假单胞菌是引起微生物角膜炎的最常见的原因之一。铜绿假单胞菌使用一种名为III型分泌系统的分子注射器，以避免通过渗透中性粒细胞而致死，从而阻止感染的清除。根据这些菌株使用其III型分泌系统注入的效应蛋白，铜绿假单胞菌可以分为两类。“细胞毒性”分离株产生ExoU和ExoT，而“侵袭性”分离株产生ExoS和ExoT。我们最近发现侵袭性铜绿假单胞菌使用exos和exoT来抑制中性粒细胞的两个主要杀菌功能，即产生活性氧和抗菌颗粒与含菌吞噬小体的融合。因此，拟议的研究计划将检查EXOS和ExoT抑制的中性粒细胞中的分子通路，以阻止活性氧物种的产生(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，通过诱导凋亡来灭活中性粒细胞，或者通过效应器介导的抑制吞噬作用。在这里，第一个被吞噬的细菌将起到毒丸的作用，使中性粒细胞失活，从而允许其他细菌茁壮成长(目标3)。因此，我们的研究计划准备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。