Susceptibility and resistance to monocytic ehrlichiosis in the mouse

To address the role of cellular immunity during ehrlichia infection, we have utilized a model of monocytic ehrlichiosis that results from infection of mice by Ixodes ovatus ehrlichia (IOE). Although ehrlichiosis in humans is largely a disease of immunocompromised individuals, the use of the IOE model has allowed us to identify factors required for host defense in normal mice. Using a low-dose infection C57BL/6 mouse model, we have demonstrated that host defense requires immune mechanisms involving CD4 T cell-mediated, TNF-alpha-, IL-12-, and IFN-gamma-dependent, macrophage activation. We have also provided formal evidence that IFN-gamma produced by CD4 Th1 cells is sufficient for protective immunity. Our recent studies have demonstrated, in addition, an essential role for IL-10, which is probably important in inhibiting immunopathological responses, and for inducible nitric oxide synthase. The latter observation establishes an important role for reactive nitrogen intermediates in bacterial elimination in vivo. In contrast, evaluation of mice carrying wild-type and mutant alleles of Nramp1 revealed at most a modest role for this gene in resistance to fatal IOE infection. Other studies in low-dose infected mice have indicated that the generation of immunological memory may be impaired during low-dose IOE infection, possibly due to bacterial immune subversion. These studies highlight the utility of the IOE mouse model in identifying important parameters of the immune response during ehrlichiosis.