The Pathogenesis of Aspergillus Keratitis

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稳步上升。虽然与免疫抑制的人口规模增加，并不是所有的真菌感染都需要一个免疫功能低下的主机。对于角膜的丝状真菌感染（即角膜炎）尤其如此，其中大多数患者是完全免疫活性的。事实上，在这种情况下，角膜病理学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，以至于42-60%的感染以角膜移植结束。在这种暗淡的临床结果改善之前，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-菌丝体相互作用的理解中的差距。使用这个模型，我们将解决的假设，居民巨噬细胞上的特异性病原体识别受体介导的中性粒细胞招募到角膜曲霉菌角膜炎（AIM 1）。在AIM 2中，我们将讨论浸润性中性粒细胞上的类似受体介导A.烟曲霉菌丝杀灭。最后，在AIM 3中，我们将讨论真菌次级代谢产物胶霉毒素通过抑制浸润中性粒细胞形成活性氧来介导真菌存活和曲霉菌角膜炎期间增强角膜病理学的假设。本文提出的研究将大大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用于治疗干预的抗炎和抗真菌靶点。Lay语言：本提案的目的是确定潜在的抗炎和抗真菌的治疗目标，在烟曲霉菌感染的角膜。我们建议通过使用A.烟曲霉角膜感染，以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死的机制。

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.