Inflammatory Responses to Aspergillus Fumigatus

对烟曲霉的炎症反应

• 批准号: 7056667
• 负责人: Kieren A. Marr
• 金额: $ 23.62万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2007-01-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056667
• 关键词: Aspergillus; apoptosis; aspergillosis; autoradiography; cell line; dendritic cells; enzyme linked immunosorbent assay; genetically modified animals; glycolipids; host organism interaction; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; phagocytosis; polysaccharides; terminal nick end labeling; toll like receptor; tumor necrosis factor alpha

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.

描述（由申请人提供）：曲霉菌是一种丝状真菌，目前是免疫功能低下患者中与感染相关的大部分死亡率的大部分。肺巨噬细胞介导了对吸入曲霉的肺曲霉的反应，肺泡巨噬细胞在孢子有机会成熟进入菌丝之前摄入并杀死分生孢子。巨噬细胞通过包括细胞因子和趋化因子的分泌的机制来协调二级反应，而树突状细胞（DCS）坐在CD4+ T淋巴细胞反应。这种反应已被认为是有益的（TH1），也可能是有害的，具有与超敏反应肺部疾病相关的主要Th2型表型。 最近的研究已经通过触发可溶性因子的巨噬细胞分泌以及诱导直流成熟的巨噬细胞分泌来介导类似Toll样的受体在介导了先天和适应性免疫的多种功能中。我们的研究表明，烟曲霉菌丝产物刺激巨噬细胞产生TNF-Alpha和IL-6，并诱导DC比分生孢子产物更成熟和Prime Th1型CD4+ T细胞。鼠巨噬细胞细胞因子分泌响应活真菌，独立于最常参与TLR介导的反应信号传导的途径（MYD88），而热杀死的菌丝产物通过MyD88依赖性途径刺激细胞因子分泌。 活菌丝产物也诱导巨噬细胞凋亡，而分生孢子则没有。为了了解这些对烟曲霉的炎症反应是如何协调的，提出了三个具体目标。特定的目标1将通过筛选多糖，甘露蛋白和糖脂细胞馏分来鉴定烟曲霉菌丝制剂的炎症成分，以在巨噬细胞系中刺激性活性。在特定的目标2中，将使用从空小鼠收集的巨噬细胞来确定TLR在中介反应中的作用。具体目标3将检验以下假设：MyD88独立的炎症反应可能与凋亡耦合。该提案利用了真菌学专家与天生和适应性免疫之间的独特合作，以实现定义对烟曲霉的免疫反应如何协调的长期目标。由于该生物是一种模型的肺部共生和病原体，因此从这些研究产生的知识也将增加我们对先天宿主防御特异性机制的理解。