The Pathogenesis of Aspergillus Keratitis

描述(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。虽然与免疫抑制的种群数量增加有关，但并不是所有的真菌感染都需要免疫受损的宿主。对于角膜的丝状真菌感染(即角膜炎)尤其如此，在这种情况下，大多数患者完全具有免疫能力。事实上，在这种情况下，角膜病理的病因是由于对入侵的有机体的过度炎症反应，而不是感染本身。在曲霉菌角膜炎期间，炎症可能非常严重，42%-60%的感染会在角膜移植后结束。在这种黯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-真菌相互作用的介体。这项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上的空白。利用这个模型，我们将提出假设，即驻留巨噬细胞上的特定病原体识别受体在曲霉菌角膜炎(AIM 1)期间介导中性粒细胞重新聚集到角膜。在目标2中，我们将解决这样的假设，即浸润性中性粒细胞上的类似受体介导了烟曲霉菌丝的杀灭。最后，在目标3中，我们将提出假设，即真菌次生代谢物，胶质毒素，通过抑制中性粒细胞渗入的活性氧的形成，在曲霉菌角膜炎期间介导真菌存活和增强角膜病理。本文提出的研究将极大地扩展我们对角膜中宿主-菌丝相互作用的理解，同时确定在曲霉菌角膜炎期间进行治疗干预的抗炎和抗真菌靶点。通俗语言：这项提案的目标是在角膜中的烟曲霉感染过程中确定潜在的抗炎和抗真菌治疗靶点。我们建议通过建立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，以及在角膜感染过程中烟曲霉逃避真菌杀灭的机制。

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.