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INTERACTION OF H CAPSULATUM WITH ALVEOLAR MACROPHAGE

H 荚膜与肺泡巨噬细胞的相互作用

基本信息

批准号：
6056339
负责人：
SIMON L. NEWMAN
金额：
$ 24.16万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2001-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6056339
关键词：
HIV infections acidity /alkalinity adenosinetriphosphatase alveolar macrophages cell growth regulation cytokine extracellular matrix proteins host organism interaction human tissue iron lung lavage lysosomes phagocytosis pulmonary surfactants respiratory infections vesicle /vacuole

项目摘要

Acquired immunodeficiency syndrome (AIDS) is an immunoregulatory disorder characterized by the presence of Kaposi's sarcoma or opportunistic infections. CD4+ T cells and mononuclear phagocytes are the target cells for the human immunodeficiency virus (HIV), the etiologic agent of AIDS. Monocyte/macrophages are a major reservoir of HIV and, therefore, a critical concern for the host is the functional capacity of monocyte/macrophages from HIV+ individuals to destroy opportunistic pathogens. Histoplasma capsulatum (Hc) is a dimorphic fungal pathogen of worldwide importance that causes a broad spectrum of disease activity. Although the course of infection is mild in most immunocompetent individuals, disseminated histoplasmosis is seen with increasing frequency as a complication of AIDS, particularly in areas where Hc is endemic. AIDS patients with disseminated histoplasmosis have a high rate of relapse even after apparently successful therapy with amphotericin B. The pulmonary alveolar monocyte/macrophage (AM) is the first line of defense following inoculation of Hc into the respiratory tract. These cells initially encounter inhaled microconidia and subsequently the transformed yeasts. The sequence of events that occur from the time that conidia enter the alveolar spaces in the lung until the appearance of numerous replicating yeasts in AN is unclear. An impairment in AM function during the initial contact with Hc could be fatal to the host. The goal of the proposed study is to gain a better understanding of the interaction of Hc yeasts and conidia with normal human AN, and with AN from patients with HIV infection. The specific aims of this proposal are: l) to quantify the capacity of AM from HIV+ individuals to bind and ingest Hc yeasts and conidia compared to AM from HIV- individuals; 2) to determine if AM from HIV+ individuals permit more rapid conversion of Hc conidia into the pathogenic yeast phase or permit more rapid multiplication of yeasts than normal AM; 3) to quantify and compare the capacity of cytokines, extracellular matrix proteins, and surfactant protein A (SP-A) to regulate the intracellular growth of Hc yeasts in normal vs. HIV-infected AM; and 4) to determine the roles of iron, the vacuolar ATPase (V-ATPase), pH, and phago-lysosomal fusion in regulating the intracellular growth of Hc yeasts in HIV- vs. HIV+ AM.

获得性免疫缺陷综合征（艾滋病）是一种免疫调节性疾病以卡波西肉瘤或机会性感染. CD 4 + T细胞和单核吞噬细胞是靶细胞人类免疫缺陷病毒（HIV），艾滋病的病原体。单核细胞/巨噬细胞是HIV的主要储存库，因此，对东道主来说，关键问题是单核细胞/巨噬细胞从HIV+个人破坏机会病原体荚膜组织胞浆菌（Histoplasma capsulatum，Hc）是一种世界性的二型真菌病原菌重要性，导致广泛的疾病活动。虽然感染过程在大多数免疫活性个体中是温和的，播散性组织胞浆菌病的发生率越来越高，艾滋病并发症，特别是在Hc流行的地区。艾滋病播散性组织胞浆菌病的患者即使在用阿替霉素B治疗明显成功后。肺泡单核/巨噬细胞（AM）是肺内防御接种后的HC进入呼吸道。这些细胞最初遇到吸入的小孢子，转化酵母事件发生的顺序，从分生孢子进入肺的肺泡腔， AN中的许多复制酵母尚不清楚。 AM受损在最初与HC接触期间的功能可能对宿主致命。拟议研究的目标是更好地了解 Hc酵母和分生孢子与正常人AN以及与AN相互作用艾滋病病毒感染者。这项建议的具体目标是： l）量化来自HIV+个体的AM结合和摄取的能力 Hc酵母和分生孢子与来自HIV-个体的AM相比; 2）确定来自HIV+个体的AM是否允许Hc更快地转化分生孢子进入致病酵母阶段或允许更快酵母菌的繁殖比正常的AM; 3）量化和比较细胞因子、细胞外基质蛋白和表面活性剂的能力蛋白A（SP-A）调节Hc酵母的细胞内生长，正常与HIV感染的AM;和4）为了确定铁的作用，液泡ATP酶（V-ATP酶）、pH和吞噬-溶酶体融合在调节 HIV-与HIV+ AM中HC酵母的细胞内生长。