Severe anemia is the most prevalent life-threatening complication of malaria infection. In addition to destruction of red blood cells (RBC), decreased RBC production or erythropoietic suppression has been shown to contribute to malarial anemia. The mechanism of this suppression is unknown, but it is considered to be multifactorial since erythropoietic suppression can be observed in the presence of both inflammatory mediators and parasite-derived factors. Experiments presented in this thesis aimed at determining the role of host cytokines released in response to blood-stage malaria infection and parasite-derived factors in erythropoietic suppression underlying the development of malarial anemia. Pro-inflammatory cytokines released during malaria infection have been proposed to play a central role in erythroid suppression. To dissect the discrete roles of these cytokines in the processes leading to anemia, mice were treated with CpG-oligodeoxynucleotides (CpG-ODN) which, like malaria infection in humans and experimental mouse models, induces an acute type 1 pro-inflammatory response. CpG-ODN treatment induced anemia, which was associated with suppressed erythropoiesis and reduced RBC survival. Importantly, CpG-ODN-induced IFN-gamma was found to be the major factor mediating erythropoietic suppression but not decreased RBC survival. We also studied the roles of Th1, Th2 and anti-inflammatory cytokines produced in response to Plasmodium chabaudi AS infection in the development of erythropoietic suppression during blood-stage malaria. Signal transducer and activator of transcription (STAT)6, required for signaling of the Th2 cytokines IL-4 and IL-13, was shown to play a critical role in malarial anemia by inhibiting the proliferation and differentiation of erythroid cells. We also observed that suppressed erythropoiesis is a general feature in mice infected with various rodent Plasmodium species that differ in their clinical manifestations and immune responses. Since parasite-derived factors have been shown to contribute to malarial pathogenesis including anemia, the contribution of P. falciparum - and P. yoelii-derived products to erythropoietic suppression was investigated. Both Plasmodium-derived and synthetic hemozoin (Hz) suppressed the proliferation but not the maturation of erythroid progenitor cells in vitro. However, P. yoelii-derived Hz but not synthetic Hz induced transient anemia in mice. These findings provide novel insights into the complex interactions between the parasite and host immune system and the regulation of erythropoiesis during severe malarial anemia.

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Thesis (D.P.H.)--University of Michigan.

Thesis (D.P.H.)--University of Michigan.