BABESIOSIS AS A PARADIGM FOR THE EFFECTS OF AGING

巴贝斯虫病是一种类似疟疾的寄生虫病，在太平洋沿岸的新英格兰、上中西部和西北部各州的发病率不断增加。在新英格兰，田鼠巴贝斯虫菌株通过莱姆病的蜱媒从田鼠传播给人类。B。在免疫正常的年轻患者中，Microti感染通常引起轻微的流感样疾病。然而，在脾切除或免疫功能低下的个体中，它导致严重的症状，临床症状从高烧到成人呼吸窘迫综合征和休克。在50岁及以上的健康人中也观察到严重的症状。因此，衰老是人类临床巴贝虫病的诱发因素。我们使用小鼠适应的B菌株开发了一种与年龄相关的人类巴贝虫病易感性小鼠模型。microti（菌株RM/NS）。将寄生的红细胞注射到“年轻”（2个月）和“年老”（18个月）的DBA/2小鼠中。通过Giemsa染色的血涂片的形态学分析确定寄生虫血症峰值和被寄生的红细胞完全清除的时间。在人类患者中，当暴露于RM/NS时，“老年”小鼠显示强烈和持续的寄生虫血症，而“年轻”小鼠具有适度和短暂的寄生虫血症。本研究项目的第一个目的是以足够的统计能力重申我们的初步研究结论，即年龄是感染小鼠模型中的一个重要变量。我们的第二个目标将是阐明这种与年龄相关的B易感性的细胞基础。显微镜我们将使用来自“年轻”和“老年”供体小鼠的全脾细胞制备物在“年轻”和“老年”辐照受体小鼠中的细胞转移研究。如果脾细胞是与年龄相关的巴贝斯虫病易感性的基础，那么从年轻小鼠中获得的整个脾细胞制剂将保护两组小鼠，而来自“老年”小鼠的细胞将无法保护任何一组。在转移至辐照受体小鼠之前，将使用阴性选择和脾细胞群的重建来确定脾T和B细胞的作用。如果年龄影响脾T细胞功能，T细胞的耗竭可能使“年轻”的脾细胞制剂不能保护“老”受体小鼠。相反，耗尽T细胞但用由B细胞、巨噬细胞和树突细胞组成的“老”脾细胞制剂重建的“年轻”脾细胞制剂将不能保护“老”受体小鼠。使用类似的方法，我们将确定年龄是否影响脾B细胞功能。这些拟议的研究可能会产生新的见解巴贝斯虫病的发病机制和免疫学变化与年龄相关，并应提供一个有用的动物模型，为未来的研究影响这些因素，如营养，抗氧化剂等。

Babesiosis is a malaria-like parasitic disease of increasing incidence in New England, the Upper Midwest and the Northwestern states of the Pacific Coast. In New England, the strain Babesiosis microti is transmitted from field mice to humans via the tick vector for Lyme disease. B. microti infection usually causes a mild, flu-like illness in young, immunologically normal patients. However, it results in severe symptoms in splenectomized or immunocompromised individuals, with clinical symptoms ranging from high fevers to adult respiratory distress syndrome and shock. Severe symptoms are also observed in otherwise healthy individuals aged 50 and above. Thus, aging is a predisposing factor for clinical babesiosis in humans. We have developed a murine model of age-related babesiosis susceptibility in humans using a mouse-adapted strain of B. microti (strain RM/NS). Parasitized red blood cells are injected into DBA/2 mice at "young" (2 month) and "old" (18 month) ages. Times of peak parasitemia and of complete clearance of parasitized red blood cells are determined by morphological analysis of Giemsa-stained blood smears As in human patients, "old" mice display an intense and sustained parasitemia, while "young" mice harbor a modest and transient parasitemia upon exposure to RM/NS. The first aim of this research project will be to reaffirm, with sufficient statistical power, our pilot study's conclusion that age is a significant variable in the murine model of infection. Our second aim will be to elucidate the cellular basis for this age-related susceptibility to B. microti. We will use cell transfer studies of whole spleen cell preparations from both "young" and "old" donor mice in both "young" and "old" irradiated recipient mice. If spleen cells are the basis of the age-related susceptibility to babesiosis, whole spleen cell preparations obtained from young mice will protect both groups of mice, while cells from "old" mice will fail to protect either group. The role of splenic T and B cells will be established using negative selection and reconstitution of spleen cell populations prior to transfer to irradiated-recipient mice. If age affects splenic T cell function, depletion of T cells may render "young" spleen cell preparations unable to protect "old" recipient mice. Conversely, "young" spleen cell preparations depleted of T cells, but reconstituted with "old" spleen cell preparations consisting of B cells, macrophages and dendritic cells will fail to protect 'old" recipient mice. Using a similar approach, we will determine whether age affects splenic B cell function. These proposed studies may yield new insights on the pathogenesis of babesiosis and immunologic changes associated with age and should provide a useful animal model for future studies of factors affecting these, such as nutrition, antioxidants, etc.