INTERACTION OF HISTOPLASMA CAPSULATUM WITH HUMAN MACROPHAGES

荚膜组织胞浆菌与人巨噬细胞的相互作用

• 批准号: 3810438
• 负责人: SIMON NEWMAN
• 金额: --
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3810438
• 关键词: Histoplasma; alveolar macrophages; antifungal agents; cytokine; fatty acid binding protein; human tissue; membrane proteins; monocyte; phagocytosis; phosphorylation; physical chemical interaction; protein kinase C; tissue /cell culture

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.

组织胞浆菌病是一种肺部感染， 来自天然来源的荚膜组织胞浆菌（Hc）的小分生孢子。 的 吸入的分生孢子存款在肺内的终端细支气管和 肺泡，并经历转化为致病酵母相。 的 原发性疾病通常是自限性的，但偶尔会演变成 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， 而这些，都是在《易经》里面， 乘。 据推测，泡状Mphi对Hc分生孢子或酵母的破坏 在感染的最初阶段， 疾病。 然而，分生孢子转化所涉及的事件 酵母是模糊的，也不清楚是否发生转化 细胞内或细胞外。 此外，人体肺泡的容量 Mphi在初次接触时杀死Hc分生孢子或酵母菌的能力尚不清楚， 特异性细胞介导激活的巨噬细胞的杀菌机制 免疫力 本研究项目的目标是详细研究 Hc与人单核/巨噬细胞的相互作用。 具体目标 本课题的主要内容是：1）确定Hc分生孢子的胞内命运 和酵母在被人单核细胞、培养的人Mphi和 人肺泡Mphi;确定介导抗真菌药物的细胞机制 活性;并确定所需的细胞因子， 激活Mphi抗真菌活性。 2)为了鉴定和纯化 LFA-1识别的Hc酵母和分生孢子上的组分， Mphi上的CR 3、p150、95粘附受体。 3)为了确定Hc是否与 Mphi LFA-1，CR 3，p150，95诱导蛋白激酶C的活化和/或 特异性膜或胞质蛋白的磷酸化。