INTERACTION OF H CAPSULATUM WITH MACROPHAGES AND PMN

描述（改编自申请人的摘要）：荚膜组织胞浆菌 (Hc) 是一种具有全球重要性的二态真菌病原体，可导致 疾病活动范围广。 虽然感染过程是 在大多数免疫功能正常的个体中，Hc 可能是轻度的，可能会产生进行性的 因血液学而免疫功能低下的个体发生播散性感染 恶性肿瘤、细胞毒治疗或患有获得性遗传病的个体 免疫缺陷综合症（艾滋病）。 Hc 感染是通过吸入小分生孢子或小分生孢子而获得的。 菌丝碎片进入肺泡。 吸入的分生孢子转化为 未知时间范围内的致病酵母阶段。 Hc 酵母是 被肺泡巨噬细胞 (AM) 吞噬，并在其中繁殖。 据推测，分裂的酵母破坏了 AM，随后被 被其他驻留 AM 以及中性粒细胞 (PMN) 和巨噬细胞 (Mo) 摄入 被招募到感染地点。 重复这个循环会导致 Hc 通过血液和淋巴管传播。 具体的成熟度 针对 Hc 的细胞介导免疫 (CMI) 激活 Mo 来阻止酵母 在大多数情况下，随着疾病过程的逐渐消退，增殖 免疫能力强的宿主。 我们研究的总体目标是了解生物学和 Hc 酵母和小分生孢子与人类相互作用的生物化学 单核细胞/Mo 和 PMN。 该提案的主要目标是：1) 定义细胞外基质（EM）蛋白和细胞因子的作用 激活Mo抗组织胞浆菌活性； 2)、识别 介导 PMN 抑菌活性的 azurophil 颗粒的成分， 定义 PMN 在宿主防御 Hc 中的体内作用，并定义 PMN 和 Mo 之间的相互作用介导宿主对 Hc 酵母的防御， 及其受 EM 蛋白和/或细胞因子的调节。 这些结果 研究应该对发病机制提供重要的见解 组织胞浆菌病并有助于设计新的治疗药物。

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.