Inflammatory Responses to Aspergillus Fumigatus

描述（由申请人提供）：烟曲霉是一种丝状真菌，目前在免疫功能低下患者中与感染相关的死亡率中占大多数。肺对吸入烟曲霉的反应是由肺泡巨噬细胞介导的，在孢子有机会成熟为菌丝之前，巨噬细胞吞噬并杀死分生孢子。巨噬细胞通过分泌细胞因子和趋化因子等机制协调次生反应，而树突状细胞（dc）协调CD4+ T淋巴细胞反应。这种反应的特点是有益的（Th1）和潜在的有害的，主要的th2型表型与过敏性肺病相关。最近的研究表明toll样受体通过触发巨噬细胞分泌可溶性因子和诱导DC成熟，介导先天免疫和适应性免疫的多种功能。我们的研究表明，与分生孢子产物相比，烟霉菌丝产物更能刺激巨噬细胞产生tnf - α和IL-6，并诱导dc成熟和初始化th1型CD4+ T细胞。小鼠巨噬细胞对活真菌的细胞因子分泌不依赖于tlr介导的信号通路（MyD88），而热杀菌丝产物通过MyD88依赖性通路刺激细胞因子分泌。活菌丝产物也会诱导巨噬细胞凋亡，而分生孢子则不会。为了了解这些对烟曲霉的炎症反应是如何协调的，提出了三个特定的目标。特异性目的1将通过筛选多糖、甘露蛋白和糖脂细胞组分来鉴定烟曲霉菌丝制剂的炎症成分，以刺激巨噬细胞系的活性。在特异性目标2中，tlr在介导反应中的作用将被确定，使用从空白小鼠中收获的巨噬细胞。特异性目的3将验证myd88非依赖性炎症反应可能与细胞凋亡耦合的假设。该建议利用真菌学专家之间的独特合作，以及先天和适应性免疫来接近定义如何协调对烟曲霉的免疫反应的长期目标。由于该生物是肺共生体和病原体的模型，从这些研究中获得的知识也将增加我们对先天宿主防御特异性机制的理解。

DESCRIPTION (provided by applicant): Aspergillus fumigatus is a filamentous fungus that currently accounts for a majority of infection-related mortality in immunocompromised patients. The pulmonary response to inhaled Aspergillus fumigatus is mediated by the alveolar macrophage, which ingests and kills conidia before the spores have a chance to mature into hyphae. Macrophages coordinate secondary responses through mechanisms that include secretion of cytokines and chemokines, whilst dendritic cells (DCs) coordinate CD4+ T lymphocyte responses. Such responses have been characterized as both beneficial (Th1), and potentially harmful, with a predominant Th2-type phenotype associated with hypersensitivity lung disease. Recent studies have implicated Toll-like receptors in mediating multiple functions of innate and adaptive immunity, both by triggering macrophage secretion of soluble factors and by inducing DC maturation. Our studies indicate that A. fumigatus hyphal products stimulate macrophages to produce TNF-alpha and IL-6, and induce DCs to mature and prime Th1-type CD4+ T cells more than conidial products. Murine macrophage cytokine secretion in response to live fungi occurs independent of the pathway most frequently involved in signaling of TLR-mediated responses (MyD88), while heat-killed hyphal products stimulate cytokine secretion through a MyD88-dependent pathway. Live hyphal products also induce macrophage apoptosis, while conidia do not. To understand how these inflammatory responses to A. fumigatus are coordinated, three specific aims are proposed. Specific Aim 1 will identify the inflammatory components of A. fumigatus hyphal preparations by screening polysaccharide, mannoprotein, and glycolipid cellular fractions for stimulatory activity in macrophage cell lines. In Specific Aim 2, the role(s) of TLRs in mediating responses will be determined, using macrophages harvested from null mice. Specific Aim 3 will test the hypothesis that MyD88-independent inflammatory responses may be coupled to apoptosis. This proposal utilizes a unique collaboration between specialists in mycology, and innate and adaptive immunity to approach the long-term goal of defining how the immune response to A. fumigatus is coordinated. As this organism is a model lung commensal and pathogen, knowledge generated from these studies will also increase our understanding of mechanisms of specificity of innate host defense.