Parasitic nematodes infect a large proportion of the world's population and contribute to the continuing poor health and economic under-development of the affected populations. Control and the planned elimination of these infections is dependent on effective anthelmintic drugs as no vaccines are available. At present, it is not properly understood how the drugs work and resistance to them is an increasing threat. It is known that many of the drugs act at receptors and ion channels in the parasites nervous system.
The aim of this proposal is to test the hypothesis that the normal processes by which these receptors and ion channels are directed to their correct locations within the cell may be subverted in resistant parasites and may be affected by the drugs themselves. Two drugs will be the focus of the studies, levamisole and emodepside. Levamisole acts at a subset of nicotinic acetylcholine receptors and emodepside at SLO-1 potassium channels. Truncated forms of subunits of the levamisole receptor have been identified and their ability to affect the location and function of the receptors will be tested in vitro and in vivo. Specific amino-acid sequence motifs that cause endocytosis from the plasma membrane are present in some truncated levamisole receptor subunits, but not the full-length versions ? the contribution of these motifs to altered trafficking will be examined. Similar motifs are present in SLO- 1 from some parasite species, but not others, which suggests that the function of the channel may be subtly different between species. This may be reflected in slightly different effects of emodepside. This will be tested by careful examination of the sub- cellular expression pattern of the different SLO-1 channels, and by testing the effects of mutating these motifs on that expression pattern. The project will reveal new aspects of the cell biology of drug targets in parasitic nematodes and provide new insights into how these may be perturbed in resistance.
This project will study the ion channels of parasitic nematodes and the way in which they might be modified to affect the effects of anthelmintic drug treatments. Truncated forms of the channels might contribute to drug resistance by changing where the channel is expressed and for how long. Signals that control this location might also explain the different effects of some drugs on different species of parasite.
