Eosinophil activation in pulmonary aspergillosis

 说明（由申请人提供）随着易感个体的数量增加，了解人类机会致病菌烟曲霉的免疫保护机制的重要性沿着迅速增加。已发表的研究结果表明，Th1反应提供了最大的保护，从A。Th2应答导致发病率和死亡率增加。最近，我们开发了一种新的感染模型，利用A。烟曲霉分离物诱导Th2-偏斜免疫，该免疫是由增加的几丁质暴露的免疫识别介导的。使用该模型，我们观察到嗜酸性粒细胞的存在导致真菌负荷和发病率增加，在血小板减少症小鼠。这些结果表明嗜酸性粒细胞是对A.烟曲霉感染与有害的Th2免疫。本项目的总体目标是进一步明确嗜酸性粒细胞在真菌感染中的作用，并确定抑制真菌感染的相关机制。 保护性免疫的发展。烟熏。我们的长期目标是确定可能在对真菌感染反应不适当的个体中靶向的途径。我们的假设是嗜酸性粒细胞活化促进了A.烟曲霉感染我们将比较曲霉病患者和实验动物的血清真菌负荷和嗜酸性粒细胞活化，以确定血清主要碱性蛋白、嗜酸性粒细胞过氧化物酶、吲哚胺2，3-双加氧酶和曲霉半乳甘露聚糖水平之间是否存在正相关。使用我们的小鼠模型，我们还将通过测定这些因素的变化来确定抗IL-5治疗的疗效，从而提供这种治疗在对感染有有害反应的曲霉病患者中的有效性的临床前评估。这些研究将确定真菌感染后保护性和有害免疫力之间平衡的关键组成部分，也有助于为患有过敏或感染的个体开发新的免疫疗法。

 DESCRIPTION (provided by applicant) The importance of understanding the mechanisms of immune protection from the human opportunistic pathogen Aspergillus fumigatus has rapidly increased along with the number of susceptible individuals. Results of published studies suggest that Th1 responses provide the most protection from A. fumigatus infection, while Th2 responses result in increased morbidity and mortality. Recently, we developed a novel infection model utilizing an A. fumigatus isolate that induced Th2-skewed immunity mediated by immune recognition of increased chitin exposure. Using this model, we observed that the presence of eosinophils resulted in increased fungal burden and morbidity in neutropenic mice. These results identified eosinophils as a potential therapeutic target in individuals that respond to A. fumigatus infection with detrimental Th2 immunity. The overall goal of this project is to further define the role of eosinophils in fungal infection and identify the related mechanisms that inhibit the development of protective immunity to A. fumigatus. Our long-term goal is to identify pathways that could be targeted in individuals that respond inappropriately to fungal infection. Our hypothesis is that eosinophil activation promotes immune pathology in A. fumigatus infection. We will compare serum fungal burden and eosinophil activation in aspergillosis patients and experimental animals to determine if a positive correlation exists between serum levels of major basic protein, eosinophil peroxidase, indoleamine 2,3-dioxygenase and Aspergillus galactomannan. Using our mouse model, we will also determine the efficacy of anti-IL-5 therapy by assaying changes in these factors, thus providing a preclinical assessment of the validity of this treatment in aspergillosis patients with detrimental responses to infection. These studies will define critical components in the balance between protective and detrimental immunity following fungal infection, and could also aid in the development of new immune therapies for individuals afflicted with allergy or infection.