Malaria is one again the number one infectious disease threatening mankind with an estimated 500 million cases worldwide and 2.3 million deaths in 1986. Of particular concern is severe anemia in children which in some malarious areas of Africa causes more pediatric deaths than cerebral malaria. Control efforts have been hampered by the emergence of insecticide resistant Anopheles mosquito vectors and of drug resistant strains of Plasmodium falciparum, the most common and deadly species infecting mankind. It has recently been suggested that an effective vaccine against asexual blood-stage forms or merozoites, which multiply in the host red blood cells and cause the clinical symptoms and pathology of malaria, would have the earliest and most dramatic impact on human morbidity and mortality. However, the immunological events resulting in control and elimination of blood-stage malaria remain incompletely understood. Although antibody-mediated immunity is considered to play a major role, the importance of cell-mediated responses, involving CD4+ T cells, macrophages and their cytokines, has recently been recognized. The studies proposed in this application are based on the hypothesis that a fulminant, lethal course of acute blood-stage malaria associated with severe anemia versus a non-lethal course is a consequence of counter- regulation by cytokines associated with CD4+ Th1 and Th2 responses. The objective of the proposed studies is to determine the role of several key immunomodulatory cytokines with counter-regulatory activities on the development of protection versus pathology during blood-stage malaria. We also propose to examine the effectiveness of a novel vaccination strategy to prevent severe and fatal malaria. The murine model of inbred mouse strains which are genetically resistant or susceptible to infection with the rodent malaria species, Plasmodium chabaudi AS, will be used to achieve these objectives.
The specific aims are: (1) to determine the role of the Th2 derived cytokines, IL4 and IL10, in the pathogenesis of severe anemia and down-regulation of protective cell-mediated immune responses during lethal blood-stage malaria; (2) to identify the role of Il12 in the generation of protective erythropoietic and immune Th1 responses in the spleen to acute blood-stage P. chabaudi AS and (3) to devise a strategy for preventing or subverting the severe and lethal consequences of malaria by vaccination with low doses of parasites, a strategy which favors the development of Th1 responses. Analysis of host defense mechanisms in the spleen, which are hypothesized to involve both extra-medullary, erythropoietic responses and activation of effector macrophages, will be carried out at the cellular and molecular levels. The rodent model of acute blood-stage P. chabaudi AS infection in well-defined inbred strains of mice, which experience either a lethal or non-lethal course of infection, should, therefore, be useful in defining the immunobiology of host-parasite interactions under genetically and environmentally controlled circumstances, conditions which are difficult to achieve in human populations.
