Drug Resistance and Pathogenic Mechanisms in P Falciparum Malaria

Wellems, T E.

Abstract

Investigations are directed at understanding (1) the mechanism of chloroquine resistance in Plasmodium falciparum malaria; (2) the expression and variation of the var gene family that modulates the adhesive and antigenic character of parasitized red blood cells; (3) a gene that is genetically linked to invasion proficiency by which malaria parasites enter red blood cells; and (4) a genetic defect of chromosome 12 that adversely affects the development of male gametocytes. The determinant of chloroquine resistance has been localized to a 36 kb segment of P. falciparum chromosome 7 in a genetic cross. DNA sequencing of this segment has identified five transcribed genes, which are being investigated in detail, to determine the mechanism of resistance. Factors responsible for the spread of drug resistance are being examined in epidemiological studies in Mali. Transfection and stable transformation of P. falciparum erythrocytic stages have been developed and are being applied to investigations of candidate chloroquine resistance genes. New selectable markers and methods to improve the efficiency and utility of the transformation are under investigation. A highly diverse family of genes (var) has been characterized that mediates antigenic variation and cytoadherence of parasitized red blood cells. Possible gene conversion events and DNA rearrangements involving telomeres have been identified as potential mechanisms that generate diversity. An unusual pool of sterile RNA transcripts (2 kb) may be involved in var gene rearrangements or expression. A novel gene, ebl-1, has been identified that is linked to invasion of red blood cells by P. falciparum. The 8 kb open reading frame encodes a molecule that is related to known ligands for sialic-acid residues at the erythrocyte surface. A defect that differentially affects the development of male gametocytes has been traced to a spontaneous mutation in a cultivated P. falciparum line. The mutation has been localized to an 800 kb segment of chromosome 12.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000483-11
• Application #: 2566780
• Study Section: Special Emphasis Panel (LPD)
• Support Year: 11
• Fiscal Year: 1996

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