INTERACTION OF H CAPSULATUM WITH MACROPHAGES AND PMN

性状（改编自申请人摘要）：荚膜组织胞浆菌 (Hc)是一种在世界范围内具有重要意义的二型真菌病原体， 广泛的疾病活动。 虽然感染的过程是 在大多数免疫功能正常的个体中，Hc为轻度， 血液学免疫功能低下个体的播散性感染 恶性肿瘤，细胞毒性治疗，或在获得性 免疫缺陷综合征（艾滋病）。 Hc的感染是通过吸入小分生孢子或 菌丝碎片进入肺泡。 吸入的分生孢子转化为 致病酵母阶段在未知的时间范围内。 HC酵母是 被肺泡巨噬细胞（AM）吞噬，在其中繁殖。 据推测，分裂的酵母破坏AM，随后被 由其他驻留AM以及中性粒细胞（PMN）和巨噬细胞（Mo）摄入 被招募到感染的地点。 重复这个循环会导致 HC通过血液和体液传播。 特定成熟度 抗Hc的细胞介导免疫（CMI）激活Mo以阻止酵母 在大多数情况下，随着疾病过程的逐渐消退， 免疫活性宿主。 我们研究的总体目标是了解生物学， Hc酵母和小分生孢子与人相互作用的生物化学 单核细胞/Mo和PMN。 这项建议的主要目标是：1）， 确定细胞外基质（EM）蛋白和细胞因子在 激活Mo抗组织胞浆菌活性;和2），鉴定 介导PMN抑真菌活性的嗜天青颗粒成分， 定义PMN在宿主防御Hc中的体内作用，并定义 中性粒细胞与钼在介导宿主防御Hc酵母中相互作用， 以及它们通过EM蛋白和/或细胞因子的调节。 的结果予以 研究应该提供重要的洞察发病机制， 组织胞浆菌病和援助的治疗新药的设计。

DESCRIPTION (adapted from the applicant's abstract): 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, Hc may produce progressive disseminated infections in individuals immunocompromised by hematological malignancies, cytotoxic therapy, or in individuals with acquired immunodeficiency syndrome (AIDS). Infection with Hc is acquired by inhalation of microconidia or small mycelial fragments into pulmonary alveoli. Inhaled conidia convert into the pathogenic yeast phase within an unknown time frame. Hc yeasts are phagocytized by alveolar macrophages (AM), within which they multiply. Presumably, the dividing yeasts destroy the AM, and subsequently are ingested by other resident AM and by neutrophils (PMN) and macrophages (Mo) recruited to the loci of infection. Repetition of this cycle results in dissemination of Hc via blood and lymphatics. Maturation of specific cell-mediated immunity (CMI) against Hc activates Mo to halt yeast proliferation with gradual resolution of the disease process in most immunocompetent hosts. The overall goal of our research is to understand the biology and biochemistry of the interactions of Hc yeasts and microconidia with human monocyte/Mo and PMN. The major objectives of this proposal are: 1), to define the role of extracellular matrix (EM) proteins and cytokines in activation Mo anti-Histoplasma activity; and 2), to identify the constituents of azurophil granules that mediate PMN fungistatic activity, to define the in vivo role of PMN in host defense against Hc, and to define the interaction between PMN and Mo in mediating host defense against Hc yeast, and their regulation by EM proteins and/or cytokines. The results of these studies should provide significant insight into the pathogenesis of histoplasmosis and aid in the design of new drugs for treatment.