INTERACTION OF H CAPSULATUM WITH ALVEOLAR MACROPHAGE

H 荚膜与肺泡巨噬细胞的相互作用

• 批准号: 2234567
• 负责人: SIMON L. NEWMAN
• 金额: $ 20.54万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2234567
• 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

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(AIDS)是一种免疫调节障碍 以出现卡波西氏肉瘤或机会主义为特征 感染。靶细胞为CD4+T细胞和单核巨噬细胞 人类免疫缺陷病毒(HIV)，艾滋病的病原体。 单核/巨噬细胞是艾滋病毒的主要宿主，因此， 主机最关心的问题是 来自HIV+个体的单核/巨噬细胞摧毁机会主义 病原体。 摘要荚膜组织胞浆菌是一种世界性的二态真菌病原体。 导致广泛疾病活动的重要性。尽管 在大多数有免疫能力的人中，感染过程是轻微的， 播散性组织胞浆菌病被认为是一种 艾滋病的并发症，特别是在HC流行的地区。艾滋病 播散型组织胞浆菌病患者的复发率甚至很高。 在两性霉素B治疗明显成功之后。 肺泡单核细胞/巨噬细胞(AM)是肺泡单核/巨噬细胞 呼吸道接种HC后的防御。这些 细胞最初遇到被吸入的微孢子，随后 转化的酵母。事件发生的顺序，从 分生孢子进入肺内的肺泡腔直到出现 目前尚不清楚在AN中是否有大量复制的酵母。AM中的损害 在最初接触HC期间的功能对宿主可能是致命的。 拟议研究的目的是更好地了解 HC酵母菌和分生孢子与正常人AN及与AN的相互作用 来自HIV感染者。这项建议的具体目标是： L)量化艾滋病病毒感染者AM结合和摄取的能力 HIV感染者的HC酵母菌和分生孢子与AM的比较；2) 确定来自HIV+个人的AM是否允许更快地转换HC 分生孢子进入致病酵母期或允许更快 酵母菌增殖率高于正常AM；3)定量比较 细胞因子、细胞外基质蛋白和表面活性物质的能力 蛋白A(SP-A)对HC酵母细胞内生长的调控 正常与感染艾滋病毒的AM；以及4)为了确定铁的作用， 空泡ATPase(V-ATPase)、pH和噬菌体融合在调节中的作用 HC酵母在HIV-VS HIV+AM中的细胞内生长