TY - JOUR
T1 - Chloroquine resistance in Plasmodium chabaudi
T2 - Are chloroquine-resistance transporter (crt) and multi-drug resistance (mdr1) orthologues involved?
AU - Hunt, Paul
AU - Cravo, P. V L
AU - Donleavy, Paul
AU - Carlton, J. M R
AU - Walliker, David
N1 - Funding Information:
We thank Richard Fawcett and Ronnie Mooney for excellent technical assistance. The work was supported by the UK Medical Research Council. P.V.L.C. was supported by the Fundaçao para a Ciencia e Tecnologia and the Centro de Malaria e Outras Doenças Tropicais, Lisbon, Portugal.
PY - 2004/1
Y1 - 2004/1
N2 - We have identified in the rodent malaria parasite Plasmodium chabaudi orthologues of two Plasmodium falciparum genes, pfcrt and pfmdr1 which have been implicated as determinants of chloroquine resistance in the latter species. The sequences of the P. chabaudi genes, denoted, respectively, pccg10 and pcmdr1, were first determined in the chloroquine-sensitive clone AS, and found to be highly similar to those of P. falciparum. For pccg10, there was a nucleotide sequence identity of 68.6% and amino acid sequence identity of 75.1% within the predicted coding region. For pcmdr1, the sequence identities were 75.0% (nucleotide) and 78.1% (amino acid). The sequences of the genes were then determined in three P. chabaudi clones selected from clone AS which possessed three different levels of resistance to chloroquine. The sequences of both genes in all mutants were found to be identical to those of the sensitive AS from which they had been derived. Polymorphic sites were found in both genes between the AS clones and a genetically unrelated sensitive clone AJ. Analysis of genetic crosses between AJ and resistant AS clones showed no linkage between inherited parental alleles of pccrt and pcmdr1 and drug responses of the cloned progeny. This showed that neither of these genes, nor genes closely linked to them, were determinants of the chloroquine resistance in the P. chabaudi mutants.
AB - We have identified in the rodent malaria parasite Plasmodium chabaudi orthologues of two Plasmodium falciparum genes, pfcrt and pfmdr1 which have been implicated as determinants of chloroquine resistance in the latter species. The sequences of the P. chabaudi genes, denoted, respectively, pccg10 and pcmdr1, were first determined in the chloroquine-sensitive clone AS, and found to be highly similar to those of P. falciparum. For pccg10, there was a nucleotide sequence identity of 68.6% and amino acid sequence identity of 75.1% within the predicted coding region. For pcmdr1, the sequence identities were 75.0% (nucleotide) and 78.1% (amino acid). The sequences of the genes were then determined in three P. chabaudi clones selected from clone AS which possessed three different levels of resistance to chloroquine. The sequences of both genes in all mutants were found to be identical to those of the sensitive AS from which they had been derived. Polymorphic sites were found in both genes between the AS clones and a genetically unrelated sensitive clone AJ. Analysis of genetic crosses between AJ and resistant AS clones showed no linkage between inherited parental alleles of pccrt and pcmdr1 and drug responses of the cloned progeny. This showed that neither of these genes, nor genes closely linked to them, were determinants of the chloroquine resistance in the P. chabaudi mutants.
KW - Chloroquine
KW - Chloroquine-resistance transporter (crt)
KW - Drug resistance
KW - Multi-drug resistance gene-1 (mdr1)
KW - Plasmodium chabaudi
KW - Plasmodium falciparum
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U2 - 10.1016/j.molbiopara.2003.08.010
DO - 10.1016/j.molbiopara.2003.08.010
M3 - Article
C2 - 14668009
AN - SCOPUS:0345096564
SN - 0166-6851
VL - 133
SP - 27
EP - 35
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
IS - 1
ER -