Genetics and Genomics of Drug Resistance and Virulence in the Malaria Parasite
Malaria is flourishing in the form of drug-resistant parasites and insecticide-resistant mosquitoes. The complexity of Plasmodium parasites’ life cycle and biology renders them elusive to drugs and vaccines. Currently, 40% of the global population is at risk for the disease. The nearly completed P. falciparum genome sequence, along with integrated, analytical tools, offers fresh hope for gene discovery and identification of novel control strategies. My lab is using methods to overlay critical biological processes on whole-genome data to bridge the gap between critical phenotypes, like drug resistance and virulence, and their underlying gene mutations, with the long-range goal of elucidating new avenues of malaria intervention.
We are focused on identifying genes that confer complex P. falciparum traits, specifically, susceptibility to antimalarial compounds and parasite proliferation in red blood cells (RBC). To do this, we study inheritance patterns of precisely measured phenotypes and high-resolution microsatellite markers to identify the genetic regions carrying genes that direct these traits’ expressions. Such quantitative trait loci (QTL) profiles act as “biological filters” of massive sequencing and transcriptional databases emerging from the genome project. In this way a biological framework can be imposed on the data to narrow the search window and to pinpoint specific genes, gene interactions, pathways and transcriptional networks that drive drug responses and parasite growth.
Parasite response to the antimalarial drug, quinine, is inherited in progeny clones of a genetic cross as a complex trait, requiring input from multiple genes (Fig. 1). Some of the loci identified for quinine susceptibility coincide with loci observed for other drug responses including chloroquine and mefloquine, a finding that points to a genetic basis for the cross-susceptibilities to these compounds observed in natural parasite populations. Knowledge of gene-by-gene interactions will be increasingly important for pinpointing complex drug response pathways (Fig. 2). My lab seeks to understand how the suites of inherited single nucleotide polymorphisms (SNPs) from genes contained within these QTL peaks converge to express a multiple-drug-resistant phenotype. This knowledge will provide insights into the nature of, and constraints on, genome-wide selection by drugs that could translate into better-targeted drug therapies and informed antimalarial drug policies.
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Cooper, R.C., M.T. Ferdig, X-z Su, L.M.B. Ursos, J. Mu, T. Nomura, H. Fujioka, D.A. Fidock, P.D. Roepe, and T.E. Wellems. Alternative mutations at position 76 of the vacuolar transmembrane protein pfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses inPlasmodium falciparum. Molecular Pharmacology, in press.
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Ferdig, M.T., R.A. Cooper, and T.E. Wellems. Malaria parasite susceptibility to quinine associated with multiple genes in a genetic cross. Genomics, submitted.