Biology, Immunology & therapy of Acanthamoeba Keratitis

生物学、免疫学

基本信息

批准号：
8132343
负责人：
Hassan Alizadeh
金额：
$ 34.45万
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/8132343
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 Generations Genes Goals Grant Health 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 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）：阿甘塔梅巴角膜炎是一种威胁性的角膜疾病，是由致病性自由活着的变形虫引起的。该研究项目的基本原理是基于以下观察结果：1）先天免疫系统在acanthamoeba角膜炎和多形核中性粒细胞（PMN）中起重要作用，是阿斯巴马木瘤角膜炎病变中明显的炎症细胞； 2）中性粒细胞在初始分辨率的阿斯塔梅巴感染中很重要； 3）腺炎角膜炎的发病机理因浸润性嗜中性粒细胞所阐述的蛋白酶加剧。 4）角膜上皮上的Toll样受体（TLR）引发了对阿斯塔梅巴感染的炎症反应。这可以通过将PMN固定在感染部位来实现； 5）角膜炎是由阿斯塔amoeba滋养体阐述的因素（初步蛋白酶）介导的组织损伤的结果； 6）寄生虫衍生的致病分子即使在滋养体上或死亡之后仍然存在； 7）寄生虫传播的致病分子与角膜表面上的几个分子反应，并诱导上皮细胞释放趋化因子和细胞因子。 8）寄生虫衍生的分子是免疫原性的，可用于引起粘膜抗体的产生，这些抗体将中和病原分子，从而减轻组织损害并减少中性粒细胞浸润。因此，PMN的保护性和破坏性作用分别影响了阿斯塔梅巴感染和疾病过程的结果。第一个具体目的将检验以下假设：角膜上皮上的Toll样受体（TLR）启动对眼部acanthamoeba感染的炎症反应。这可以通过固定最初杀死阿斯塔木瘤或有助于疾病发病的PMN来实现。第二个具体目的将检验以下假设：甘露糖诱导的 - acanthamoeba细胞质蛋白（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）激活的新型途径释放凋亡和蛛网膜酸释放。第三个特定目的将检验以下假设：acanthamoeba滋养体构成表达PLA2，该pla2可以直接诱导对角膜上皮细胞的细胞病变作用，或激活磷脂并诱导蛛网膜酸释放。第四个特定目的将检验以下假设：用PLA2抑制剂治疗和MIP-133免疫将减轻阿甘达莫巴角膜炎的发病机理。该项目的远距离目标是评估阿斯塔梅巴角膜炎的致病机制，这些机制可能会对改善代表最严重治疗困难的阿斯塔amoeba患者的疗法产生巨大影响。公共卫生相关性：该项目的远距离目标是评估阿斯塔amoeba角膜炎的致病机制，这些机制可能会对改善代表最严重的治疗困境的acanthamoeba患者的疗法产生巨大影响。