Molecular Genetics of Drug Resistance and Red Cell Invasion in Malaria

Wellems, T E.

Abstract

Our investigations concern the resistance of Plasmodium falciparum to several common antimalarial drugs: the dihydrofolate reductase inhibitor pyrimethamine, and the quinoline ring derivatives chloroquine, quinidine and mefloquine. We are crosses of cloned parasite lines to identify the genes that affect susceptibility to these drugs. Point mutations in the gene encoding dihydrofolate reductase-thymidylate synthase have been found to confer pyrimethamine resistance in malaria. Chloroquine resistance has been found to be governed by a single gene in linkage studies. RFLP analysis is being to pinpoint the location of this gene. A similar approach is being used to identify affecting erythrocyte- stage proliferation. In a cross between two clones the faster proliferation rate of one parent predominated in progeny recovered after cross fertilization and infection of chimpanzees. Linkage group analysis suggests an association between a genetic locus near a telomere of chromosome 13 and the rapid proliferation rate. Investigations are now planned to map the genes involved and examine for relationship to sialic acid and erythrocyte-binding proteins thought to modulate erythrocyte invasion by P. falciparum.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000483-04
• Application #: 3818257
• Support Year: 4
• Fiscal Year: 1988

Institution

• Name: Niaid Extramural Activities
• Country: United States

Publications

Cholera, Rushina; Brittain, Nathaniel J; Gillrie, Mark R et al. (2008) Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci U S A 105:991-6

Hayton, Karen; Gaur, Deepak; Liu, Anna et al. (2008) Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion. Cell Host Microbe 4:40-51

Su, Xinzhuan; Hayton, Karen; Wellems, Thomas E (2007) Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nat Rev Genet 8:497-506

Djimde, A A; Kirkman, L; Kassambara, L et al. (2007) [In vitro cultivation of fields isolates of Plasmodium falciparum in Mali] Bull Soc Pathol Exot 100:3-5

Sa, Juliana Martha; Yamamoto, Marcio M; Fernandez-Becerra, Carmen et al. (2006) Expression and function of pvcrt-o, a Plasmodium vivax ortholog of pfcrt, in Plasmodium falciparum and Dictyostelium discoideum. Mol Biochem Parasitol 150:219-28

Fairhurst, Rick M; Wellems, Thomas E (2006) Modulation of malaria virulence by determinants of Plasmodium falciparum erythrocyte membrane protein-1 display. Curr Opin Hematol 13:124-30

Rohrbach, Petra; Sanchez, Cecilia P; Hayton, Karen et al. (2006) Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J 25:3000-11

Sa, Juliana Martha; Nomura, Takashi; Neves, Joana d'Arc et al. (2005) Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains. Exp Parasitol 109:256-9

Furuya, Tetsuya; Mu, Jianbing; Hayton, Karen et al. (2005) Disruption of a Plasmodium falciparum gene linked to male sexual development causes early arrest in gametocytogenesis. Proc Natl Acad Sci U S A 102:16813-8

Wang, Xinhua; Mu, Jianbing; Li, Guoqiao et al. (2005) Decreased prevalence of the Plasmodium falciparum chloroquine resistance transporter 76T marker associated with cessation of chloroquine use against P. falciparum malaria in Hainan, People's Republic of China. Am J Trop Med Hyg 72:410-4