Interaction of H. capsulatum with Dendritic Cells

荚膜梭菌与树突状细胞的相互作用

• 批准号: 6896119
• 负责人: SIMON L. NEWMAN
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896119
• 关键词: CD28 molecule; CD40 molecule; Histoplasma; T lymphocyte; antigen presentation; antigen presenting cell; cellular immunity; clinical research; cytokine; dendritic cells; disease /disorder model; histoplasmosis; host organism interaction; human subject; laboratory mouse; lung disorder; lymphocyte proliferation; macrophage; monocyte; phagocytosis; phlebotomy; tissue /cell culture; yeasts

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.

描述（由申请人提供）：荚膜组织胞浆菌（Hc）是一种具有全球重要性的二态性真菌病原体，可引起广泛的疾病活动。虽然大多数免疫功能正常的个体的感染过程较轻，但 Hc 可能会在因血液恶性肿瘤、细胞毒治疗而免疫功能低下的个体或患有获得性免疫缺陷综合征 (AIDS) 的个体中产生进行性播散性感染。 Hc 感染是通过将小分生孢子吸入肺泡而获得的。分生孢子转化为致病性酵母阶段，酵母被肺泡巨噬细胞（AM）吞噬。分裂的酵母会破坏 AM，然后它们被其他 AM 以及炎症性中性粒细胞和巨噬细胞 (M-phi) 摄取。重复这个循环会导致 Hc 通过血液和淋巴管传播。针对 Hc 的特异性细胞介导免疫 (CMI) 的成熟会激活 M-phi 来阻止酵母增殖，从而逐渐解决疾病过程。 尽管树突状细胞 (DC) 是免疫系统中最有效的抗原呈递细胞 (APC)，并且对于 CMI 的诱导至关重要，但它们在宿主防御真菌中的作用在很大程度上被忽视了。本研究的总体目标是了解 Hc 与 DC 相互作用的生物学和生物化学，并表征 DC 在诱导 Hc 保护性免疫中的作用。该提案的主要目标是： 1) 确定鼠肺 DC 是否摄入并限制 Hc 分生孢子转化为酵母。具体来说，我们将确定肺 DC 是否吞噬 Hc 分生孢子，确定识别是否是通过 VLA-5，确定分生孢子的细胞内命运，识别 Hc 感染的 DC 产生的细胞因子，并确定为什么 Hc 被 M-phi 和 DC 上的不同受体识别。 2) 确定 Hc 感染的 DC 和 T 细胞之间抗原呈递在 T 细胞增殖、细胞因子产生和共刺激分子需求方面的功能相关性，并确定 DC-Hc-T 细胞相互作用是否产生激活 M-phi 抗组织胞浆菌活性的细胞因子。 3) 确定Hc抗原脉冲的DC是否在肺组织胞浆菌病小鼠模型中赋予保护性免疫，并确定免疫功能正常和免疫功能低下的小鼠的保护性免疫的免疫学参数。这些研究的结果将为组织胞浆菌病的发病机制提供重要的见解，并有助于设计预防疾病的新型疫苗策略。