INTERACTION OF HISTOPLASMA CAPSULATUM WITH HUMAN MACROPHAGES

组织胞浆菌病是一种因吸入 来自天然来源的组织胞浆菌(HC)的微孢子。这个 吸入性分生孢子沉积在终末细支气管内的肺部和 肺泡，并转化为致病酵母相。这个 原发疾病通常是自限性的，但偶尔会演变为 慢性空洞型。在实验动物中，可以检测到HC酵母菌 在吸入分生孢子后36小时内的肺部感染区域， 并且只存在于巨噬细胞(Mphi)中，在巨噬细胞中酵母 乘法。据推测，肺泡菌对HC分生孢子或酵母菌的破坏 在感染的最早阶段就会毁掉这个机构 疾病的威胁。然而，分生孢子转化过程中涉及的事件 对酵母的影响尚不清楚，也不清楚是否会发生转化。 胞内或胞外。此外，人肺泡灌洗液容量 在初次相遇时杀死HC分生孢子或酵母菌的Mphi是未知的，正如所说的那样 特异性细胞介导的巨噬细胞激活的杀菌机制 豁免权。这项研究项目的目标是详细检查 HC与人单核/巨噬细胞的相互作用具体目标 该项目的主要内容是：1)确定HC分生孢子在细胞内的命运 和酵母对人单核细胞的吞噬作用，培养的人Mphi，和 人肺泡巨噬细胞介导抗真菌的细胞机制 对HC的活性；以及确定所需的细胞因子 激活Mphi抗真菌活性。2)鉴定和提纯 LFA-1识别的HC酵母菌和分生孢子上的成分(S)， Mphi表面CR3、P150、95黏附受体。3)确定HC是否绑定到 Mphi LFA-1、CR3、P150、95诱导蛋白激酶C和/或 特异膜蛋白或胞质蛋白的磷酸化。

Histoplasmosis is a pulmonary infection acquired by inhalation of microconidia of Histoplasma capsulatum (Hc) from natural sources. The inhaled conidia deposit in the lung within the terminal brochioles and alveoli, and undergo transformation into the pathogenic yeast phase. The primary disease is generally self-limited, but occasionally evolves into a chronic cavitary form. In experimental animals, Hc yeasts can be detected in infected areas of the lung within 36 hr after inhalation of the conidia, and are present exclusively in macrophages (Mphi), within which the yeasts multiply. Presumably, destruction of Hc conidia or yeasts by alveolar Mphi during the earliest phase of the infection would abrogate the establishment of disease. However, the events involved in the transformation of conidia to yeasts are obscure, and it is not clear whether transformation occurs intra- or extracellularly. In addition, the capacity of human alveolar Mphi to kill Hc conidia or yeasts upon initial encounter is unknown, as is the fungicidal mechanism of macrophages activated by specific cell-mediated immunity. The objectives of this research project are to examine in detail the interaction of Hc with human monocyte/macrophages. The specific aims of the project are: 1) To determine the intracellular fate of Hc conidia and yeasts upon phagocytosis by human monocytes, cultured human Mphi, and human alveolar Mphi; to define cellular mechanisms that mediate antifungal activity against Hc; and to identify the cytokines that are required to activate Mphi antifungal activity. 2) To identify and purify the component(s) on Hc yeasts and conidia that are recognized by the LFA-1, CR3, p150, 95 adhesion receptors on Mphi. 3) To determine if Hc binding to Mphi LFA-1, CR3, p150, 95 induces activation of protein kinase C and/or phosphorylation of specific membrane or cytosolic proteins.