Limited genetic variation in the Plasmodium falciparum heme detoxification protein (HDP)

Sumiti Vinayak, Dharmendar Rathore, Simon Kariuki, Laurence Slutsker, Ya Ping Shi, Leopoldo Villegas, Ananias A. Escalante, Venkatachalam Udhayakumar

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Malaria parasites infecting host red blood cells degrade hemoglobin by detoxifying heme into hemozoin. This conversion of heme to hemozoin is performed by a potent protein called heme detoxification protein (HDP), making HDP an attractive target for antimalarial drug development. We studied the genetic variation in Plasmodium falciparum HDP and also investigated if HDP due to its involvement in the heme detoxification pathway is under any potential chloroquine (CQ) selection pressure. We sequenced the complete HDP gene encompassing three exons and two introns (AT and ATTT repeats in intron 1; AT repeats in intron 2) from five P. falciparum laboratory strains with known CQ sensitivity and 50 field isolates from Venezuela (n = 26) and Kenya (n = 24), with high levels of CQ resistance. Sequencing revealed two mutations, C41F and F91L in exon 1 and exon 2, respectively. The F41 mutation was present only in the CQ sensitive (CQS) HB3 strain. However, all the isolates harbored the 91L mutation, except for the CQS 3D7 strain. The sequencing of the intron 2 region revealed no variation in the number of AT repeats. In contrast, there was a wide variation in the AT and ATTT repeats in intron 1. Overall with respect to the intron 1 repeats, the Venezuelan isolates (Expected heterozygosity, He = 0.685) showed less genetic variation as compared to the Kenyan isolates (He = 0.986). Furthermore, we also genotyped the 72-76 codons of the pfcrt gene but did not observe any correlation of the pfcrt CQ resistant genotypes (SVMNT or CVIET) with variation in the HDP, thus indicating HDP not to be under any CQ selection pressure. In conclusion, HDP is a conserved target for future antimalarial development.

Original languageEnglish (US)
Pages (from-to)286-289
Number of pages4
JournalInfection, Genetics and Evolution
Volume9
Issue number2
DOIs
StatePublished - Mar 1 2009

Keywords

  • AT/ATTT repeats
  • Chloroquine (CQ)
  • Chloroquine resistant (CQR)
  • Chloroquine sensitive (CQS)
  • Heme detoxification protein (HDP)
  • Intron 1
  • Plasmodium falciparum

ASJC Scopus subject areas

  • Microbiology
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Microbiology (medical)
  • Infectious Diseases

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