The broad long-term objective of this proposal is to understand the mechanistic basis of anemia caused by Plasmodium. To reach this objective, we will develop Macaca mulatto (rhesus macaque) and Aotusnon- human primate experimental model systems to address immediate questions as well as hypotheses that develop in the course of this project. Malarial anemia in non-human primates manifests with characteristics that are very similar to anemia observed in patients infected with Plasmodium, and,similarly, differs with acute and chronic infections and depending upon the immune status of the host. Plasmodium cynomolgi and P. coatmyi infections in M. mulatto monkeys are comparable to human malaria infections caused by P. vivax and P. falciparum, respectively, and,similarly, can result in the development of moderate and severe anemia. The development of the rhesus monkey model will allow the most in depth study of the underlying basis of malarial anemia, to quantitatively assess the degree to which the premature destruction of normal red blood cells, ineffective erythropoiesis, and dyserythropoiesis are major factors. The roles of cytokines and other immunopathogenic factors will also be investigated. P. falciparum infections of Aotus monkeys, on the other hand, are currently important models for the testing of malaria vaccines. Chronic moderate to low-level or sub-patent parasitemias are observed in these animals with frequent but varied degrees of moderate to severe anemia, which is poorly understood. The specific aims of the proposed studies are to 1) establish and rigorously evaluate kinetic measurements of clinical, hematological, parasitological, and immunological parameters to determine the molecular mechanistic basis of malarial anemia in rhesus macaque monkeys experimentally infected with P. coatneyi and P. cynomolgi; models for P. falciparum and P. vivax infection in humans, respectively; and 2) examine and compare the mechanistic basis of malarial anemia observed in experimentally vaccinated Aotus nancymai monkeys that are exposed to homologous challenge and heterologous re-challenge with P. falciparum.