Dr Barbara Reaves
In residence at
Dr Cédric Neveu
Intracellular trafficking of anthelmintic drug targets and its contribution to drug resistance
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 project 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. The focus of the studies is nicotinic acetylcholine receptors, which are targets of many anthelmintic drugs. Truncated forms of subunits of the acetylcholine receptor affect the location and function of the receptors in vitro. 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, both in cultured cell lines and in genetically modified worms. The project will reveal new aspects of the cell biology of drug targets in nematodes and provide new insights into how these may be perturbed in resistance. It is part of a continuing collaboration between the University of Georgia and INRAE, Nouzilly.