P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus.
Ivermectin (IVM) is the only safe drug for mass-treatment of onchocerciasis. IVM resistance has been reported in gastrointestinal nematode parasites of animals. A reduction in response to IVM in Onchocerca volvulus could have significant consequences for the onchocerciasis control programs. We have found evidence that, in O. volvulus, repeated IVM treatment selects for specific alleles, of P-glycoprotein-like protein (PLP), a half-sized ABC transporter. In this study, O. volvulus samples were derived from a clinical trial in Cameroon, in which patients were sampled before, and following 3 years (1994-1997) of IVM treatments. There were four treatment groups: 150 microg/kg (1 x p.a. or 4 x p.a.) and 800 microg/kg (1 x p.a. or 4 x p.a.). DNA of O. volvulus macrofilariae was genotyped over a 476bp region of the PLP gene and at two control genes. Of the six polymorphic positions found in the PLP amplicon, three of them showed significant selection after 4 x p.a. treatment with IVM (total of 13 IVM treatments) in female worms, and one of the same single nucleotide polymorphisms (SNPs) showed significant selection in the male worms. One of the selected SNPs in the female worms caused an amino acid coding change in the putative protein sequence. We found a clear selection of some genotypes, a high SNPs association and a loss of polymorphism following 4 x p.a. treatment with IVM. These PLP SNPs and genotypes could be useful markers to follow selection for IVM resistance in the field.
Bourguinat
Catherine
C
Institute of Parasitology, McGill University, 21 111 Lakeshore Road, Sainte Anne-de-Bellevue, Quebec, Canada H9X3V9.
Ardelli
Bernadette F
BF
Pion
Sébastien D S
SD
Kamgno
Joseph
J
Gardon
Jacques
J
Duke
Brian O L
BO
Boussinesq
Michel
M
Prichard
Roger K
RK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002163:Cameroon; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology*; D015810:Linkage Disequilibrium; D008297:Male; D008969:Molecular Sequence Data; D017181:Onchocerca volvulus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009855:Onchocerciasis / Q000188:drug therapy / Q000469:parasitology; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000977:Antiparasitic Agents; D005819:Genetic Markers; D015801:Helminth Proteins; D007559:Ivermectin