INTERACTION OF H CAPSULATUM WITH MACROPHAGES AND PMN

描述(改编自申请人的摘要)：组织胞浆菌 (HC)是一种具有世界重要性的二态真菌病原体，可引起 疾病活动的广谱。尽管感染的过程是 在大多数免疫能力强的人中，HC可能会产生进行性的 血液病患者免疫功能受损的播散性感染 恶性肿瘤，细胞毒治疗，或获得性 免疫缺陷综合征(艾滋病)。 吸入微孢子或小孢子可感染丙型肝炎病毒 菌丝碎片进入肺泡。吸入分生孢子转化为 在未知时间范围内的致病酵母相。HC酵母是 被肺泡巨噬细胞(AM)吞噬，在其中繁殖。 据推测，分裂的酵母菌破坏AM，随后是 由其他常驻AM、中性粒细胞(PMN)和巨噬细胞(Mo)摄取 被招募到感染地点。这个循环的重复会导致 丙型肝炎病毒通过血液和淋巴管传播。特定的成熟度 抗HC的细胞免疫(CMI)激活钼抑制酵母 在大多数情况下，随着疾病过程的逐渐解决而扩散 有免疫能力的宿主。 我们研究的总体目标是了解生物学和 HC酵母和微孢子与人相互作用的生物化学 单核细胞/钼和中性粒细胞。这项建议的主要目标是：1)、 明确细胞外基质(EM)蛋白和细胞因子在 激活钼抗组织胞浆体活性；2)，鉴定 介导PMN抑菌活性的天青颗粒的成分，以 明确PMN在宿主抵抗HC中的体内作用，并定义 PMN和Mo在介导宿主对HC酵母防御中的相互作用， 以及EM蛋白和/或细胞因子对它们的调节。这些研究的结果 研究应提供重要的洞察力的发病机制 组织胞浆菌病和协助设计新的治疗药物。

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.