Bourguinat Catherine, Ardelli Bernadette F, Pion Sébastien D S, Kamgno Joseph, Gardon Jacques, Duke Brian O L, Boussinesq Michel, Prichard Roger K
Institute of Parasitology, McGill University, 21 111 Lakeshore Road, Sainte Anne-de-Bellevue, Quebec, Canada H9X3V9.
Mol Biochem Parasitol. 2008 Apr;158(2):101-11. doi: 10.1016/j.molbiopara.2007.11.017. Epub 2007 Dec 14.
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.
伊维菌素（IVM）是大规模治疗盘尾丝虫病的唯一安全药物。动物胃肠道线虫寄生虫中已报道有对IVM产生耐药性的情况。盘尾丝虫对IVM反应的降低可能会对盘尾丝虫病控制项目产生重大影响。我们发现有证据表明，在盘尾丝虫中，重复使用IVM治疗会选择特定的P-糖蛋白样蛋白（PLP，一种半大小的ABC转运蛋白）等位基因。在本研究中，盘尾丝虫样本来自喀麦隆的一项临床试验，其中患者在接受IVM治疗3年（1994 - 1997年）之前和之后进行采样。有四个治疗组：150微克/千克（每年1次或每年4次）和800微克/千克（每年1次或每年4次）。对盘尾丝虫成虫的DNA在PLP基因的476bp区域以及两个对照基因上进行基因分型。在PLP扩增子中发现的六个多态性位点中，其中三个在雌性蠕虫中经每年4次IVM治疗（总共13次IVM治疗）后显示出显著的选择，并且相同的单核苷酸多态性（SNP）之一在雄性蠕虫中显示出显著的选择。雌性蠕虫中一个被选择的SNP在推定的蛋白质序列中导致了氨基酸编码变化。我们发现经过每年4次IVM治疗后，某些基因型有明显的选择、SNP高度关联且多态性丧失。这些PLP SNPs和基因型可能是追踪野外IVM耐药性选择的有用标记。
