The Pathogenesis of Aspergillus Keratitis

曲霉菌性角膜炎的发病机制

基本信息

批准号：
7923157
负责人：
Sixto Manuel Leal
金额：
$ 3.29万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923157
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Antifungal Agents Apoptosis Aspergillosis Aspergillus Aspergillus fumigatus Class Zygomycetes Clinical Cornea Data Disease Etiology Fusarium Gliotoxin Goals Host Defense Human Hyphae ITGB2 gene Immune Immune response Immunocompetent Immunocompromised Host Immunologic Receptors Incidence Infection Inflammation Inflammatory Inflammatory Response Invaded Keratitis Keratoplasty Knockout Mice Language Leukocytes Lung Mediating Mediator of activation protein Modeling Mus Mycelium Mycoses Neutrophil Infiltration Organism Outcome Pathogenesis Pathology Patients Population Sizes Production Reactive Oxygen Species Research Role Severity of illness Site TLR2 gene TLR4 gene Testing Therapeutic Intervention Tissues Yeasts cytokine dectin 1 extracellular fungus immunosuppressed improved in vivo insight killings macrophage microbicide mouse model mutant neutrophil novel pathogen receptor therapeutic target toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): The incidence of human fungal infections has steadily increased over the past few decades. Though associated with an increased immunosuppressed population size, not all fungal infections necessitate an immunocompromised hosts. This is especially true for filamentous fungal infections of the cornea (i.e keratitis), in which the majority of patients are fully immunocompetent. Indeed, in such cases the etiology of corneal pathology is due to an excessive inflammatory response to the invading organism, not the infection itself. During Aspergillus keratitis, the inflammation can be so severe that 42-60% of infections end with corneal transplantation. Before such bleak clinical outcomes improve, we must invest in research to better understand the mediators of host-fungai interactions. This proposal will utilize a murine corneal infection model (i.e Aspergillus keratitis) to address gaps in our current understanding of in vivo host-mycelia interactions. Using this model, we will address the hypothesis that specific pathogen recognition receptors on resident macrophages mediate neutrophil recruitment into the cornea during Aspergillus keratitis (AIM 1). In AIM 2 we will address the hypothesis that similar receptors on infiltrating neutrophils mediate A. fumigatus hyphal killing. Lastly, in AIM 3 we will address the hypothesis that the fungal secondary metabolite, gliotoxin, mediates fungal survival and enhanced corneal pathology during Aspergillus keratitis through inhibition of reactive oxygen species formation by infiltrating neutrophils. The studies proposed herein will greatly expand our understanding of host-mycelial interactions in the cornea, while identifying anti-inflammatory and anti-fungal targets for therapeutic intervention during Aspergillus keratitis. Lay Language: The goal of this proposal is to identify potential anti-inflammatory and anti-fungal therapeutic targets during Aspergillus fumigatus infection in the cornea. We propose to do this by using mouse models of A. fumigatus corneal infection to study the innate immune receptors required for recognition and killing of this fungus, as well as the mechanism by which A.fumigatus evades fungal killing during corneal infection.

描述（由申请人提供）：过去几十年来，人类真菌感染的发病率稳步上升。尽管与免疫抑制群体规模的增加有关，但并非所有真菌感染都需要免疫功能低下的宿主。对于角膜丝状真菌感染（即角膜炎）尤其如此，大多数患者具有完全的免疫能力。事实上，在这种情况下，角膜病理的病因是由于对入侵微生物的过度炎症反应，而不是感染本身。在曲霉菌性角膜炎期间，炎症可能非常严重，以至于 42-60% 的感染最终以角膜移植结束。在这种暗淡的临床结果得到改善之前，我们必须投资于研究，以更好地了解宿主与真菌相互作用的介质。该提案将利用小鼠角膜感染模型（即曲霉菌角膜炎）来解决我们目前对体内宿主菌丝体相互作用的理解中的空白。使用该模型，我们将解决这样的假设：常驻巨噬细胞上的特定病原体识别受体在曲霉角膜炎期间介导中性粒细胞募集到角膜中（AIM 1）。在 AIM 2 中，我们将提出这样的假设：浸润性中性粒细胞上的类似受体介导烟曲霉菌丝杀伤。最后，在 AIM 3 中，我们将提出这样的假设：真菌次级代谢产物胶霉毒素通过浸润中性粒细胞抑制活性氧的形成，介导曲霉菌角膜炎期间的真菌存活并增强角膜病理。本文提出的研究将极大地扩展我们对角膜中宿主菌丝体相互作用的理解，同时确定曲霉菌角膜炎期间治疗干预的抗炎和抗真菌靶点。外行语言：该提案的目标是确定角膜烟曲霉感染期间潜在的抗炎和抗真菌治疗靶点。我们建议通过使用烟曲霉角膜感染的小鼠模型来研究识别和杀死这种真菌所需的先天免疫受体，以及烟曲霉在角膜感染期间逃避真菌杀灭的机制。