| The inability to acquire protective immunity against Plasmodia is a chief obstacle to malaria control and the goal of this thesis research is to identify factors that prevent the development of persistent and protective immunity against malaria. High levels of inflammatory cytokines have been shown to inhibit memory T cell development in viral infections, and the studies described herein reveals that inflammatory cytokines also impact the development of protective immunity during blood stage Plasmodium infection. This work characterizes the formation of CD4 T cell-mediated immunological memory during protozoan infections and contributes to the understanding of immunity against other complex infections.;In addition to describing the role of inflammatory cytokines during malaria, the work in this thesis also identifies a Plasmodium strategy for modulating the host inflammatory responses to blood stage malaria. Examination of malaria patient samples and experiments in murine malaria models revealed a novel inflammatory function of the Plasmodium-encoded ortholog of the mammalian cytokine, macrophage migration inhibitory factor (MIF). Plasmodium MIF expression was associated with inflammatory sequelae in human malaria, and murine infections with genetically manipulated P. berghei reveal that Plasmodium MIF can regulate inflammation and immunity during blood stage malaria. The findings presented here indicate that high concentrations of circulating Plasmodium MIF during blood stage malaria results in an increased initial immune response and a diminished CD4 T cell-mediated recall response. These results are the first to implicate a Plasmodium-encoded protein in modulating the adaptive immune response and interfering with the generation of malaria-specific memory CD4 T cells, thereby facilitating parasite persistence and transmission. The immunoregulatory function of PMIF may account for its expression across all Plasmodium species and for the evolutionary conservation of MIF in numerous protozoan and helminthic parasites. Targeting PMIF may be a useful approach for augmenting natural host immunity and developing more effective vaccines. |
