Biology, Immunology & therapy of Acanthamoeba Keratitis

生物学、免疫学

基本信息

批准号：
7736084
负责人：
Hassan Alizadeh
金额：
$ 36.25万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2014-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7736084
关键词：
Acanthameba infection Acanthamoeba Acanthamoeba Keratitis Adaptor Signaling Protein Amoeba genus Antibodies Apoptosis Arachidonic Acids Biology Cell Nucleus Cell membrane Cell physiology Cells Chinese Hamster Cornea Corneal Diseases Cytolysis Disease Epithelial Cells Equilibrium Event Figs - dietary Generations Genes Goals Grant Human Immune response Immune system Immunization Immunology In Vitro Induction of Apoptosis Infection Infection Control Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Keratitis Lead Lesion Life Ligands Lipoxygenase MAPK14 gene MAPK8 gene Mannose Mediating Mediator of activation protein Membrane Membrane Fluidity Mitogen-Activated Protein Kinases Modification NF-kappa B Neutrophil Infiltration Outcome Parasites Pathogenesis Pathway interactions Patients Peptide Hydrolases Phase Phospholipase A2 Phospholipids Play Procedures Process Production Prostaglandin-Endoperoxide Synthase Protein Kinase C Proteins Recruitment Activity Research Project Grants Resolution Role Severity of illness Signal Pathway Signal Transduction Site Surface Testing Therapeutic Therapeutic procedure Tissues Toll-like receptors Transcription Factor AP-1 Transcriptional Activation Vision base chemokine corneal epithelium cytokine design human PLA2G2A protein immunogenic immunopathology improved in vivo insight killings neutrophil novel phospholipase A2 inhibitor prevent public health relevance receptor function toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Acanthamoeba keratitis is a sight-threatening corneal disease caused by pathogenic free-living amoebae. The rationale for this research project is based on the following observations: 1) The innate immune system plays an important role in Acanthamoeba keratitis and polymorphonuclear neutrophils (PMN) are the prominent inflammatory cells in Acanthamoeba keratitis lesions; 2) neutrophils are important in initial resolution of Acanthamoeba infection; 3) pathogenesis of Acanthamoeba keratitis is exacerbated by the protease elaborated by infiltrating neutrophils; 4 ) Toll-like receptors (TLRs) on the corneal epithelium initiate the inflammatory responses to Acanthamoeba infections. This may be achieved by immobilizing PMN at the site of infection; 5) keratitis is the consequence of tissue damage mediated by factors (preliminary proteases) elaborated by Acanthamoeba trophozoites; 6) parasite- derived pathogenic molecules persist even after trophozoites encyst or die; 7) parasite-borne pathogenic molecules react with several molecules on the surface of the cornea and induce the release of chemokines and cytokines by the epithelial cells; 8) parasite-derived molecules are immunogenic and can be used to elicit the production of mucosal antibodies that will neutralize the pathogenic molecules and thus, mitigate tissue damage and reduce neutrophil infiltration. Thus, the protective and destructive roles of PMNs influence the outcome of Acanthamoeba infection and disease processes respectively. The first specific aim will test the hypothesis that Toll-like receptors (TLRs) on the corneal epithelium initiate the inflammatory responses to ocular Acanthamoeba infections. This may be achieved by immobilizing PMNs that either initially kill Acanthamoeba or contribute to the pathogenesis of the disease. The second specific aim will test the hypothesis that the mannose induced- Acanthamoeba cytopathic protein (MIP-133) interacts with phospholipids on the corneal epithelial cells and induces both apoptosis and arachidonic acid release through a novel pathway involving phospholipase A2 (PLA2) activation. The Third specific aim will test the hypothesis that Acanthamoeba trophozoites constitutively express PLA2 that either directly induces cytopathic effects on the corneal epithelial cells or activates phospholipids and induces arachidonic acid release. The forth specific aim will test the hypothesis that treatment with PLA2 inhibitors and immunization with MIP-133 will mitigate the pathogenesis of Acanthamoeba keratitis. The long-range goal of this project is to evaluate the pathogenic mechanisms of Acanthamoeba keratitis that could have an enormous impact on designing improved therapies for Acanthamoeba patients that represent the most serious therapeutic dilemmas. PUBLIC HEALTH RELEVANCE: The long-range goal of this project is to evaluate the pathogenic mechanisms of Acanthamoeba keratitis that could have an enormous impact for designing improved therapies for Acanthamoeba patients that represent the most serious therapeutic dilemmas.

描述（由申请人提供）：棘阿米巴角膜炎是一种由致病性自由生活阿米巴引起的威胁视力的角膜疾病。该研究项目的基本原理基于以下观察：1）先天免疫系统在棘阿米巴角膜炎中发挥重要作用，多形核中性粒细胞（PMN）是棘阿米巴角膜炎病变中的主要炎症细胞； 2) 中性粒细胞对于棘阿米巴感染的初步解决很重要； 3) 棘阿米巴角膜炎的发病机制是由浸润性中性粒细胞产生的蛋白酶加剧的； 4）角膜上皮上的Toll样受体（TLR）启动对棘阿米巴感染的炎症反应。这可以通过将 PMN 固定在感染部位来实现； 5) 角膜炎是由棘阿米巴滋养体产生的因子（初级蛋白酶）介导的组织损伤的结果； 6) 即使在滋养体包囊或死亡后，源自寄生虫的致病分子仍然存在； 7）寄生虫携带的致病分子与角膜表面的多种分子发生反应，诱导上皮细胞释放趋化因子和细胞因子； 8) 寄生虫衍生的分子具有免疫原性，可用于引发粘膜抗体的产生，从而中和致病分子，从而减轻组织损伤并减少中性粒细胞浸润。因此，PMN 的保护作用和破坏作用分别影响棘阿米巴感染和疾病过程的结果。第一个具体目标将检验角膜上皮上的 Toll 样受体 (TLR) 启动对眼部棘阿米巴感染的炎症反应的假设。这可以通过固定 PMN 来实现，PMN 要么最初杀死棘阿米巴，要么促进该疾病的发病机制。第二个具体目标将检验以下假设：甘露糖诱导的棘阿米巴细胞病变蛋白 (MIP-133) 与角膜上皮细胞上的磷脂相互作用，并通过涉及磷脂酶 A2 (PLA2) 激活的新途径诱导细胞凋亡和花生四烯酸释放。第三个具体目标将检验棘阿米巴滋养体组成型表达 PLA2 的假设，PLA2 直接诱导对角膜上皮细胞的细胞病变作用或激活磷脂并诱导花生四烯酸释放。第四个具体目标将检验以下假设：PLA2 抑制剂治疗和 MIP-133 免疫将减轻棘阿米巴角膜炎的发病机制。该项目的长期目标是评估棘阿米巴角膜炎的致病机制，这可能对为代表最严重治疗困境的棘阿米巴患者设计改进的疗法产生巨大影响。公共健康相关性：该项目的长期目标是评估棘阿米巴角膜炎的致病机制，这可能对为代表最严重治疗困境的棘阿米巴患者设计改进的疗法产生巨大影响。