GENETICS OF DRUG RESISTANCE AND PATHOGENIC MECHANISMS IN P FALCIPARUM MALARIA

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Of the four Plasmodium species generally responsible for human malaria, Plasmodium falciparum produces the most severe disease and causes almost all deaths. P. falciparum also has become resistant to chloroquine, once the first-line drug for the prophylaxis and treatment of malaria. The Malaria Genetics Section of the Laboratory of Parasitic Diseases conducts basic research on factors that govern the drug response, pathogenesis and transmission of P. falciparum malaria. For more than a decade, a principal theme in this work has been the search for the gene responsible for chloroquine resistance. This search has required development of previously nonexistent genetic resources and technology, including P. falciparum pedigrees for linkage analysis, detailed microsatellite linkage maps of the genome and gene transformation methods for erythrocyte-stage parasites. Current research in the Section includes the following projects: 1) the mechanisms of chloroquine resistance and quinine resistance in P. falciparum malaria; 2) targets of other leading antimalarial drugs, including such dihydrofolate-reductase (DHFR) inhibitors such as pyrimethamine, WR99210, proguanil and cycloguanil; 3) the expression and variation of the var genes which modulate the adhesive and antigenic character of parasitized red blood cells; 4) hemoglobinopathies and severity of malaria in African children; 5) a genetic defect of chromosome 12 that adversely affects the development of male gametocytes; 6) function of ebl-1, a candidate gene for an invasion phenotype linked to P.falciparum chromosome 13.