Interaction of H. capsulatum with Dendritic Cells

描述（由申请人提供）：荚膜组织浆体（Hc）是一种具有世界重要性的二态真菌病原体，可引起广泛的疾病活动。尽管在大多数免疫能力强的个体中，感染过程是轻微的，但在因血液恶性肿瘤、细胞毒性治疗或获得性免疫缺陷综合征（艾滋病）的个体中，丙型肝炎可能产生进行性播散性感染。Hc感染是通过吸入微孢子进入肺泡而获得的。分生孢子转化为致病酵母期，酵母被肺泡巨噬细胞（AM）吞噬。分裂的酵母破坏AM，然后它们被其他AM、炎症性中性粒细胞和巨噬细胞（M-phi）吸收。这种循环的重复导致Hc通过血液和淋巴传播。针对Hc的特异性细胞介导免疫（CMI）的成熟激活M-phi以阻止酵母增殖，并逐渐解决疾病过程。

DESCRIPTION (provided by applicant): 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 hematologic malignancies, cytotoxic therapy, or in individuals with the acquired immunodeficiency syndrome (AIDS). Infection with Hc is acquired by inhalation of microconidia into the pulmonary alveoli. The conidia convert into the pathogenic yeast phase, and yeasts are phagocytized by alveolar macrophages (AM). Dividing yeasts destroy the AM, and then they are ingested by other AM, and by inflammatory neutrophils and macrophages (M-phi). Repetition of this cycle leads to dissemination of Hc via blood and lymphatics. Maturation of specific cell-mediated immunity (CMI) against Hc activates M-phi to halt yeast proliferation with gradual resolution of the disease process. Although, dendritic cells (DC) are the most potent antigen-presenting cells (APC) of the immune system, and are critical for the induction of CMI, their role in host defense against fungi has been largely ignored. The overall goal of the proposed research is to understand the biology and biochemistry of the interaction of Hc with DC, and to characterize the role of DC in the induction of protective immunity to Hc. The major objectives of the proposal are: 1) To determine if murine lung DC ingest and restrict the conversion of Hc conidia into yeasts. Specifically we will determine if lung DC phagocytose Hc conidia, determine if recognition is via VLA-5, determine the intracellular fate of conidia, identify the cytokines produced by Hc-infected DC, and determine why Hc is recognized by different receptors on M-phi and DC. 2) To identify the functional correlates for antigen presentation between Hc-infected DC and T cells with respect to T cell proliferation, cytokine production, and the requirement for co-stimulatory molecules, and to determine if DC-Hc-T cell interaction produces cytokines that activate M-phi anti-histoplasma activity. 3) To determine if Hc antigen-pulsed DC confer protective immunity in a murine model of pulmonary histoplasmosis, and to define the immunologic parameters of protective immunity in immunocompetent and immunocompromised mice. The results of these studies should provide significant insight into the pathogenesis of histoplasmosis and aid in the design of novel vaccine strategies for the prevention of disease.