Ivermectin resistance and overview of the Consortium for AnthelminticResistance SNPs

Abstract

Ivermectin (IVM) has transformed nematode parasite control in veterinary medicineand the control of some nematode infections in humans, such as onchocerciasais,lymphatic filariasis in Africa and strongyloidiasis. Unfortunately, IVMresistance is now a serious problem for parasite control in livestock and thereis a concern about resistance development and spread in nematode parasites ofhumans. IVM is believed to act by opening glutamate-gated chloride channels andGABA-gated channels in invertebrate neurons or muscle cells, leading tohyperpolarisation of the cells and to an inhibitory paralysis. However, in thefilarial nematodes, it is not altogether clear that the effect of IVM isconfined to these actions or even whether these are the most important.Alterations in some ligand-gated ion channel (LGIC) receptor subunits may play arole in the mechanisms of IVM resistance in some nematodes, but the evidencethat changes in LGICs are the most important cause of IVM resistance innematodes is far from clear. What is evident is that IVM is an excellentsubstrate for some ATP-binding cassette transporters, IVM selects for changes inexpression levels of ABC transporters, such as P-glycoproteins, and that alteredlevels of some ABC transporters contribute to IVM resistance. In addition, thereis growing evidence that IVM selects on β-tubulin, at least in somenematodes. Based on these various mechanisms, which contribute to IVMresistance, it may become possible to develop panels of molecular markers forIVM resistance in different nematode parasites. In order to stimulate thedevelopment of such markers, an international Consortium for AnthelminticResistance SNPs (CARS) has been developed to help coordinate marker development,advance our knowledge of helminth biology and possibly assist with thedevelopment of new anthelmintic molecules.