Histoplasma capsulatum Ligands for Dendritic Cell VLA-5

囊状组织胞浆菌(HC)是一种具有世界重要意义的二态真菌病原体，可引起广泛的疾病活动。尽管大多数有免疫能力的人感染过程轻微，但在因血液系统恶性肿瘤、细胞毒治疗或获得性免疫缺陷综合征(AIDS)而免疫受损的人中，HC可能会产生进行性播散性感染。感染HC是通过吸入微孢子进入肺泡，在那里它们转化为致病酵母期。针对HC的特异性细胞免疫的成熟需要树突状细胞(DC)、巨噬细胞和T细胞之间的复杂相互作用，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，这些功能是由特定的受体-配体相互作用调节的。这项提议的目的是确定HC酵母和巨噬细胞和DC之间的受体-配体相互作用如何调节致病和宿主防御。我们已经确定CD18是巨噬细胞上识别HC酵母的受体，而纤维连接蛋白受体非常晚期抗原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。这项建议的主要目的是：1)将亲环素A定性为DC VLA-5的粘附素；2)确定亲环素A在HC酵母与DC和巨噬细胞相互作用中的免疫调节作用；以及3)确定亲环素的缺失如何影响HC感染的过程。 小鼠肺组织胞浆菌病模型，以及亲环素是否刺激保护性免疫。从这些研究中获得的知识将为组织胞浆菌病的发病机制、宿主防御提供重要的洞察力，并为开发预防组织胞浆菌病的新疫苗策略奠定基础。

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.