Pathogenesis of falciparum malaria in infancy

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DESCRIPTION (provided by the applicant): Malaria kills 1 million African children each year. However, although all infants in holoendemic areas develop parasitemia frequently, only 10 percent develop severe anemia, the commonest cause of death. We previously showed that parasite adhesion and anti-adhesion antibodies explain susceptibility and resistance to pregnancy malaria. Because the parasites infecting children have binding phenotypes distinct from those infecting adults, we hypothesize that a similar paradigm explains the pathogenesis of infancy malaria. We propose a longitudinal study of infants from birth through age 3. We will examine samples for: 1) P. falciparum adhesion phenotype; 2) anti-adhesion antibodies; 3) presence of parasites in hemoglobin (Hb)Fvs HbA-containing (i.e., fetal vs. maternal) red cells; 4) levels of p-amino benzoic acid (PABA), HbF, and antibodies. We will test our primary hypothesis that parasite binding and anti-adhesion antibodies predict severe infancy malaria. In addition, we will examine a secondary hypothesis that neonates are resistant to malaria because their vasculature does not support parasite binding. Based on our hypotheses, we expect the following results: 1) parasite adhesion phenotypes change with host age; 2) anti-adhesion antibodies protect infants from parasites with the corresponding adhesion phenotype; 3) parasite binding patterns and specific anti-adhesion antibodies predict protection from severe anemia; 4) cord blood parasites will bind CSA, and parasites will appear exclusively in HbA-containing red cells of neonates; 5) the genotype and binding phenotype will differ between cord blood isolates and isolates obtained at the time of an infant's first infection. We will examine other factors for their effect on malaria, including transpiacentally transferred maternal antibodies, HbF, and PABA levels, and we will determine HIV status as a potential confounder in these studies. If breastfeeding confers resistance to malaria by limiting PABA intake, this will influence the debate on whether HIV-infected women in tropical areas should breastteed. These studies will establish the roles of parasite adhesion and anti-adhesion antibodies in the pathogenesis of infancy malaria, and may identify new targets for antimalarial therapies in children. Identifying new therapies for children is an urgent public health goal, but is not a funding priority for the United States Department of Defense.