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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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，烟曲霉现在被认为是受损个体中主要的空气传播真菌病原体。免疫力正常的人即使暴露于高浓度的分生烟曲霉也很少发生曲霉病，而多形核中性粒细胞（PMN）的几种缺陷被认为是该病的一个重要危险因素。为了研究PMN在肺部的防御作用，特别是其抗氧化活性，我们将正常小鼠PMN对烟曲霉病的反应与gp91phox缺陷和cxcr2缺陷小鼠进行了比较，这些小鼠对曲霉病易感。在gp91phox缺陷小鼠中，NADPH氧化酶是失活的，而在cxcr2缺陷小鼠中，对某些炎症刺激的PMN募集延迟。在正常balb/c小鼠中，招募PMN通过将分生孢子封闭在PMN聚集物中来抑制萌发，并通过甲醛染色检测氧化酶活性。gp91phox缺陷小鼠的分生孢子萌发发生在PMN聚集形成但缺乏氧化酶活性的小鼠中，而cxcr2缺陷小鼠的分生孢子萌发发生在氧化酶活性的PMN聚集形成延迟的小鼠中。我们的研究提供了体内证据，表明虽然到达免疫能力小鼠肺部的一些分生孢子被肺泡巨噬细胞（AM）参与，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。对cxcr2缺陷和gp91phox缺陷小鼠的实验表明，这些事件必须在孢子暴露后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能力强的人即使暴露于大量分生孢子中也没有疾病。未来的研究将更好地描述PMN和AM中分生孢子杀伤的分子机制。