Histoplasma capsulatum Ligands for Dendritic Cell VLA-5

荚膜组织浆体（Hc）是一种世界范围内重要的二态真菌病原体，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感染是通过将微孢子吸入肺泡而获得的，在肺泡中它们转化为致病酵母菌期。针对Hc的特异性细胞介导免疫的成熟需要树突状细胞（DC）、巨噬细胞和T细胞之间复杂的相互作用，最终导致巨噬细胞的激活和疾病过程的解决。我们假设肺巨噬细胞中的Hc复制是Hc传播能力的基础，DC杀死Hc酵母的能力导致保护性免疫的发展，这些功能受到特异性受体-配体相互作用的调节。本提案的目的是确定Hc酵母与巨噬细胞和DC之间的受体-配体相互作用如何调节发病机制和宿主防御。我们已经确定CD18是巨噬细胞上识别Hc酵母的受体，纤维连接蛋白受体晚抗原5 （VLA-5）是DC上识别Hc酵母的受体。最近，我们发现热休克蛋白60 （hsp60）是巨噬细胞CD18识别的Hc配体。本提案的主要目标是：1)表征Hc亲环蛋白A作为DC vla5的粘附素；2)确定亲环蛋白A在Hc酵母与DC和巨噬细胞相互作用中的免疫调节作用；3)确定a型肝炎病毒中亲环蛋白的缺失对丙型肝炎病毒感染过程的影响

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 where they convert into the pathogenic yeast phase. Maturation of specific cell-mediated immunity against Hc requires a complex interaction between dendritic cells (DC), macrophages, and T cells that eventually leads to activation of macrophages and resolution of the disease process. We hypothesize that Hc replication in macrophages of the lung is the basis for the ability of Hc to disseminate, that the ability of DC to kill Hc yeasts leads to the development of protective immunity, and that these functions are regulated by specific receptor-ligand interactions. The goal of this proposal is to determine how receptor-ligand interaction between Hc yeasts and macrophages and DC regulates pathogenesis and host defense. We have identified CD18 as the receptors on macrophages that recognize Hc yeasts, and the fibronectin receptor very late antigen 5 (VLA-5) as the receptor on DC that recognizes Hc yeasts. Most recently we identified heat shock protein 60 (hsp60) as the Hc ligand recognized by macrophage CD18. The major objectives of this proposal are: 1), to characterize Hc cyclophilin A as an adhesin for DC VLA-5; 2), to define the immunoregulatory role of cyclophilin A with respect to the interaction of Hc yeasts with DC and macrophages; and 3), to determine how the absence of cyclophilin influences the course of Hc infection in a murine model of pulmonary histoplasmosis, and if cyclophilin stimulates protective immunity. Knowledge gained from these studies will provide significant insight into the pathogenesis of histoplasmosis, host defense, and a basis for the development of novel vaccine strategies for the prevention of histoplasmosis.