MT VET COBRE PROJECT 3: NEUTROPHIL FUNCTION IN ASPERGILLOSIS IMMUNITY

MT VET COBRE 项目 3：曲霉病免疫中的中性粒细胞功能

• 批准号: 7382192
• 负责人: JAMES B BURRITT
• 金额: $ 20.27万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382192
• 关键词: MT; VET; COBRE; PROJECT; NEUTROPHIL

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aspergillus fumigatus is a fungus that causes fatal infection in humans. Recent decades have seen increasing numbers fatal A. fumigatus infections in patients with immune suppressive disorders, and A. fumigatus is now recognized as the leading airborne fungal pathogen in compromised individuals. Humans with normal immunity rarely develop aspergillosis even when exposed to high concentrations of A. fumigatus conidia, and several deficiencies of polymorphonuclear neutrophils (PMN) are recognized to be a significant risk factor in this disease. In order to study the defensive role of PMN in the lungs, with particular reference to their antimicrobial oxidant activity, responses of PMN to A. fumigatus conidia in normal mice were compared to those in gp91phox-deficient and CXCR2-deficient mice, which are susceptible to aspergillosis. In gp91phox-deficient mice NADPH oxidase is inactive while in CXCR2-deficient mice there is delayed PMN recruitment in response to certain inflammatory stimuli. In normal balb/c mice, recruited PMN inhibited germination by enclosure of conidia within PMN aggregates where oxidase activity was detected with formazan staining. Conidial germination occurred in gp91phox-deficient mice, where PMN aggregates formed but lacked oxidase activity and in CXCR2-deficient mice, where there was a delay in formation of oxidase-active PMN aggregates. Our studies provide in vivo evidence to indicate that while some conidia reaching the lungs of immune competent mice are engaged by alveolar macarophages (AM), recruitment, activation and formation of oxidase-active PMN aggregates around conidia inhibited additional germination. Experiments using CXCR2-deficient and gp91phox-deficient mice indicate that it is essential for these events to occur within 6 h following conidial exposure to prevent hyphal emergence. This information may help explain a lack of disease in immunocompetent humans, even when exposed to large numbers of conidia. Future studies will better describe the molecular mechanisms of conidial killing in both PMN and AM.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。烟曲霉是一种引起人类致命感染的真菌。近几十年来，免疫抑制性疾病患者中致命的烟曲霉感染数量不断增加，烟曲霉现已被认为是受损个体中主要的空气传播真菌病原体。即使暴露于高浓度的烟曲霉分生孢子，具有正常免疫力的人类也很少患曲霉病，并且多形核中性粒细胞（PMN）的多种缺陷被认为是该疾病的重要危险因素。为了研究 PMN 在肺部的防御作用，特别是其抗微生物氧化活性，将正常小鼠中 PMN 对烟曲霉分生孢子的反应与 gp91phox 缺陷和 CXCR2 缺陷小鼠（易感）进行了比较。曲霉菌病。在 gp91phox 缺陷的小鼠中，NADPH 氧化酶失去活性，而在 CXCR2 缺陷的小鼠中，PMN 募集因某些炎症刺激而延迟。在正常 balb/c 小鼠中，招募的 PMN 通过将分生孢子封闭在 PMN 聚集体中来抑制发芽，其中通过甲臜染色检测氧化酶活性。分生孢子萌发发生在 gp91phox 缺陷型小鼠中，其中 PMN 聚集体形成，但缺乏氧化酶活性；而在 CXCR2 缺陷型小鼠中，氧化酶活性 PMN 聚集体形成延迟。我们的研究提供的体内证据表明，虽然一些到达免疫活性小鼠肺部的分生孢子被肺泡巨噬细胞（AM）吸引，但分生孢子周围氧化酶活性PMN聚集体的募集、激活和形成抑制了额外的萌发。使用 CXCR2 缺陷和 gp91phox 缺陷小鼠进行的实验表明，这些事件必须在分生孢子暴露后 6 小时内发生，以防止菌丝出现。这一信息可能有助于解释免疫功能正常的人类即使接触大量分生孢子也不会患疾病。未来的研究将更好地描述 PMN 和 AM 中分生孢子杀灭的分子机制。