The Pathogenesis of Aspergillus Keratitis

曲霉菌性角膜炎的发病机制

基本信息

批准号：
8128621
负责人：
Sixto Manuel Leal
金额：
$ 3.36万
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/8128621
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）：在过去的几十年中，人类真菌感染的发病率一直在稳步增加。尽管与免疫抑制的人口大小相关，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（即角膜炎）的丝状真菌感染尤其如此，其中大多数患者完全具有免疫能力。确实，在这种情况下，角膜病理学的病因是由于对入侵生物的过度炎症反应，而不是感染本身。在角膜炎中，炎症可能非常严重，以至于42-60％的感染以角膜移植结束。在这种黯淡的临床结果改善之前，我们必须投资研究以更好地了解宿主 - 芬加互动的调解人。该提案将利用鼠角膜感染模型（即角膜炎）来解决我们当前对体内宿主膜相互作用的理解中的差距。使用此模型，我们将解决以下假设：在角膜炎曲霉曲霉期间，居民巨噬细胞上的特定病原体识别受体介导嗜中性粒细胞募集到角膜中（AIM 1）。在AIM 2中，我们将解决以下假设：浸润性嗜中性粒细胞的类似受体介导粉状曲霉菌丝杀伤。最后，在AIM 3中，我们将解决以下假设：真菌二次代谢产物神经毒素，通过抑制中性粒细胞抑制活性氧形成，从而介导了曲霉角膜炎期间的真菌生存和增强的角膜病理学。本文提出的研究将大大扩展我们对角膜中宿主膜相互作用的理解，同时鉴定出抗炎和抗真菌靶标在角膜炎期间进行治疗干预的靶标。外行语言：该提案的目的是确定角膜曲霉感染曲霉感染期间潜在的抗炎和抗真菌治疗靶标。我们建议通过使用烟曲霉的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A.fumigatus逃避角膜感染期间真菌杀死的机制。