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.
| Vannier, Edouard; Borggraefe, Ingo; Telford 3rd, Samuel R et al. (2004) Age-associated decline in resistance to Babesia microti is genetically determined. J Infect Dis 189:1721-8 |
