A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum.
The emerging resistance to quinine jeopardizes the efficacy of a drug that has been used in the treatment of malaria for several centuries. To identify factors contributing to differential quinine responses in the human malaria parasite Plasmodium falciparum, we have conducted comparative quantitative trait locus analyses on the susceptibility to quinine and also its stereoisomer quinidine, and on the initial and steady-state intracellular drug accumulation levels in the F1 progeny of a genetic cross. These data, together with genetic screens of field isolates and laboratory strains associated differential quinine and quinidine responses with mutated pfcrt, a segment on chromosome 13, and a novel candidate gene, termed MAL7P1.19 (encoding a HECT ubiquitin ligase). Despite a strong likelihood of association, episomal transfections demonstrated a role for the HECT ubiquitin-protein ligase in quinine and quinidine sensitivity in only a subset of genetic backgrounds, and here the changes in IC50 values were moderate (approximately 2-fold). These data show that quinine responsiveness is a complex genetic trait with multiple alleles playing a role and that more experiments are needed to unravel the role of the contributing factors.
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Cecilia P
CP
Sanchez
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Chia-Hao
CH
Liu
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Sybille
S
Mayer
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany; Laboratory for the Development of Agroindustrial and Biomedical Technology (LAPTIAB), Tangerang Selatan, Indonesia.
Astutiati
A
Nurhasanah
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Marek
M
Cyrklaff
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
Jianbing
J
Mu
The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
Michael T
MT
Ferdig
Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
Wilfred D
WD
Stein
Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Michael
M
Lanzer
D000818:Animals; D002874:Chromosome Mapping; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006056:Golgi Apparatus / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D011803:Quinine; D044767:Ubiquitin-Protein Ligases; D011802:Quinidine