Genetics of Drug Resistance and Pathogenic Mechanisms in P Falciparum Malaria

Wellems, T E.

Abstract

Of the four Plasmodium species generally responsible for human malaria, Plasmodium falciparum produces the most severe disease and almost all deaths. P. falciparum also has become resistant to chloroquine, once the first-line drug for the prophylaxis and treatment of malaria, so that death rates are returning to historic levels in many areas of Africa. Research in the Malaria Genetics Sections is conducted to understand the factors that determine the drug responses, virulence and transmission of P. falciparum malaria and thereby provide a foundation for new diagnostics and therapeutic measures against the disease. Current efforts include projects on 1) the mechanism of chloroquine resistance in Plasmodium falciparum malaria; 2) alternative antimalarial compounds that block the dihydrofolate-reductase (DHFR) target of the drugs pyrimethamine and cycloguanil; 3) the expression and variation of the var gene family that modulates the adhesive and antigenic character of parasitized red blood cells; 4) occurrence of severe malaria in African children who carry the hemoglobin C mutation; and 5) a genetic defect of chromosome 12 that adversely affects the development of male gametocytes.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000483-12
• Application #: 6160618
• Study Section: Special Emphasis Panel (LPD)
• Support Year: 12
• Fiscal Year: 1997

Institution

• Name: National Institute of Allergy and Infectious Diseases
• 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