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Mechanisms of flagellin-induced protection against microbial keratitis

鞭毛蛋白诱导的微生物性角膜炎保护机制

基本信息

批准号：
8840592
负责人：
Fu-Shin X Yu
金额：
$ 37.24万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840592
关键词：
Acetylation Adjuvant Anti-Inflammatory Agents Anti-inflammatory Antibiotic Resistance Aspergillus Biological Assay Blindness Bone Marrow Candida Candida albicans Cells Chromatin Cornea Data Dendritic Cells Development Epithelial Epithelial Cells Epithelium Flagellin Gene Expression Genes Genomics Goals Grant Histone Deacetylase Inhibitor Homeostasis Hour Immune Immune response Infection Inflammation Inflammation Mediators Inflammatory Invaded Keratitis Knock-out Knockout Mice Knowledge Lead Ligands Light Mediating Mediator of activation protein Methods Modality Modeling Molecular Structure Mucosal Immunity Mus Myeloid Cells Natural Immunity Neutrophil Infiltration Play Production Pseudomonas aeruginosa Recovery of Function Recruitment Activity Regulation Resistance Resistance to infection Role Severities Signal Transduction Small Interfering RNA TLR2 gene Testing Therapeutic Toll-Like Receptor 5 Toll-like receptors Topical application Transgenic Mice activating transcription factor 3 antimicrobial peptide base cathelicidin chemokine chromatin immunoprecipitation chromatin modification chromatin remodeling corneal epithelium cytokine innovation macrophage microbial mouse model neutrophil ocular surface pathogen prevent promoter prophylactic reconstitution response transcription factor

项目摘要

Microbial keratitis is a common cause of vision loss. The cornea is exquisitely sensitive to inflammation- mediated damage and therefore has strong innate defenses. However, when the epithelial barrier function is breached, opportunistic bacterial and fungal pathogens can gain access to the epithelial cell layers and colonize in the cornea, leading to infection. During the initial grant period, flagellin, the ligand of Toll-like receptor 5 (TLR5), was used to fortify corneal innate immunity and render resistance to a broad spectrum of keratitis causing pathogens, including Pseudomonas aeruginosa, Candida albicans and Aspergillus fumigates. This highly inducible and robust innate mucosal protection can be attributed to flagellin-induced genomic reprogramming in the epithelium which, in turn, interacts with professional immune cells to control inflammation and to eradicate invading pathogens. The hypothesis in this application is that flagellin, through TLR5, stimulates protective corneal innate mucosal immunity that involves epithelial cells, infiltrated PMNs, and activated dendritic cells, collectively conferring robust resistance to microbial keratitis. Three specific aims are proposed to test this hypothesis: 1) To determine how flagellin-induced reprogramming is regulated in corneal epithelial cells and in the cornea. This can be assessed by using the chromatin immunoprecipitation assay and histone deacetylase inhibitors for gene-specific chromatin modification and by using siRNA and knockout mice for delineating the role of activating transcription factor-3, a transcription factor induced by fg, in regulating the innate immune response in the cornea. 2) To determine how the epithelium participates in and coordinates flagellin-induced mucosal innate immune defense against microbial keratitis. The role of the epithelium and its interaction with dendritic cells in innate defense will be determined by using various transgenic and knockout mice, bone marrow reconstitution, and cell depletion. 3) To determine how flagellin induces protection against non-flagellated pathogens in the cornea. The therapeutic potential of flagellin and its mechanisms of action will be characterized by using mouse models of fungal keratitis (Candida and Aspergillus as pathogens and post-infection topical flagellin application) and double TLR knockout mice. The results of the proposed study should shed light on corneal innate immunity and its induction, and may lead to the development of new prophylactic/therapeutic modalities for preventing and treating microbial keratitis.

细菌性角膜炎是视力丧失的常见原因。角膜对炎症非常敏感