The Pathogenesis of Aspergillus Keratitis

描述（由申请人提供）：在过去的几十年里，人类真菌感染的发病率稳步上升。虽然与免疫抑制群体规模增加有关，但并非所有真菌感染都需要免疫功能低下的宿主。对于丝状真菌感染的角膜（即角膜炎）尤其如此，其中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生物体的过度炎症反应，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，42-60%的感染以角膜移植结束。在这种惨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-真菌相互作用的介质。该建议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-菌丝相互作用的理解空白。利用该模型，我们将探讨在曲霉菌性角膜炎（AIM 1）期间，巨噬细胞上的特异性病原体识别受体介导中性粒细胞向角膜募集的假设。在AIM 2中，我们将讨论浸润中性粒细胞上的类似受体介导烟曲霉菌丝杀死的假设。最后，在AIM 3中，我们将讨论真菌次生代谢物胶质毒素通过抑制浸润中性粒细胞形成活性氧来介导曲霉菌角膜炎期间真菌存活和增强角膜病理的假设。本文提出的研究将极大地扩展我们对角膜中宿主-菌丝相互作用的理解，同时确定曲霉菌性角膜炎治疗干预的抗炎和抗真菌靶点。本提案的目的是在角膜烟曲霉感染期间确定潜在的抗炎和抗真菌治疗靶点。我们拟利用烟曲霉角膜感染小鼠模型，研究该真菌识别和杀伤所需的先天免疫受体，以及烟曲霉在角膜感染过程中逃避真菌杀伤的机制。

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.