Genetic control of malaria parasite proliferation

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Proliferation of Plasmodium falciparum in red blood cells (RBC) forms the basis for the tertian fever cycles characteristic of the most devastating form of human malaria. High asexual multiplication rate during the erythrocytic phase of the life cycle is associated with severe disease. Blood stage P. falciparum parasites can be maintained in cultured RBC, and thus in vitro cultivation is the cornerstone of research into parasite biology, invasion-blocking vaccine development, and drug effects. Although the basic steps of parasite growth in RBC are well characterized, the genes and molecular events controlling these processes are poorly understood. A classical genetic approach using modern genomics tools offers a unique way to find these determinants. The goal of this research is to exploit a high-resolution microsatellite linkage map along with measurements of in vitro growth-related traits to find loci controlling these phenotypes. Identified loci can be used to target the emerging P. falciparum sequence data in a biologically relevant way to identify mechanisms of parasite multiplication in RBC. The hypothesis of this proposal is that complex 'growth rate' is comprised of simpler discrete steps that can be measured and mapped, leading to efficient use of genome databases to pinpoint growth-related genes. The initial investigation of this hypothesis was to quantify heritable differences in the proliferation rate of progeny rates of the HB3xDd2 cross using the incorporation of radiolabeled hypoxanthine to quantify parasite growth. Quantitative trait loci (QTL) mapping of the trait has identified significant effects from genes on chromosomes 9 and 13. Specific Aim 1 is to precisely measure traits that underlie the growth rate, including efficiency and selectivity of RBC invasion by merozoites produced per schizogony and culture synchronicity. In Specific Aim 2, the genetically controlled variation in these traits will be characterized and localized in the genome by QTL mapping to build a profile of nested effects and positions of important genes. Specific Aim 3 will use microsatellite markers delimiting prominent QTL peaks to positionally QTL peaks to positionally mine existing P. falciparum genome sequence and gene transcription data for candidate genes. These studies represent a novel approach to overlay important biological processes on whole genome data, with the goal of elucidating new avenues for malaria intervention.