Eosinophil activation in pulmonary aspergillosis

 描述(由申请人提供)随着易感个体的数量的增加，了解针对人类机会性病原体烟曲霉的免疫保护机制的重要性迅速增加。已发表的研究结果表明，Th1应答对烟曲霉菌的感染提供了最大的保护，而Th2应答会导致发病率和死亡率的增加。最近，我们利用一株烟曲霉菌建立了一种新的感染模型，该模型通过对甲壳素暴露增加的免疫识别来诱导Th2偏斜免疫。使用这个模型，我们观察到嗜酸性粒细胞的存在导致中性粒细胞减少的小鼠的真菌负荷和发病率增加。这些结果确定嗜酸性粒细胞是对有害Th2免疫的烟曲霉菌感染有反应的个体的潜在治疗靶点。这个项目的总体目标是进一步确定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。 烟曲霉菌保护性免疫的研究进展我们的长期目标是确定可以针对对真菌感染反应不当的个人的途径。我们的假设是嗜酸性粒细胞的激活促进了烟曲霉菌感染的免疫病理。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激活，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-双加氧酶和半乳甘露聚糖之间是否存在正相关。利用我们的小鼠模型，我们还将通过分析这些因素的变化来确定抗IL-5治疗的有效性，从而为对感染有不利反应的曲霉病患者提供这种治疗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免疫和有害免疫之间平衡的关键成分，并可能有助于为过敏或感染患者开发新的免疫疗法。

 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.