Understanding the mechanism of a nematode molecular Achilles' heel.

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Parasitic nematodes are major challenges to human health and global food security. The impact of these animals is exacerbated by drug resistance, withdrawal of existing treatments due to environmental concerns, and expansion of parasites into new environments through climate change and human migration. There is thus an urgent need to develop new control methods. Ideal targets for the development of new therapeutics would be molecules and processes that are found only in nematodes and are absent from the animals and plants that they infect. Ideally these targets would be found in all nematodes, enabling the development of a drug active against a broad range of nematode infections. One such process is spliced leader trans-splicing, which is an essential step by which many nematode genes become active.We have shown that two 'molecular machines' are required for spliced leader trans-splicing. Nematodes in which these machines are non-functional stop developing and are infertile. However, we don't have the detailed knowledge of these machines needed to understand how they function, a necessary precondition to properly develop drugs that inhibit them. In particular, we don't know all the components involved, and we don't understand those that we do know about. To address these challenges, we are systematically studying the components of these machines in the experimental nematode Caenorhabditis elegans. Our work so far has led to the identification of a new component which has properties that make it an ideal potential drug target. The proposed research will extend our initial studies, to give a comprehensive picture of the molecular machinery that underpins this essential step in nematode gene expression. The process of spliced leader trans-splicing has evolved multiple times in different groups of organisms, many of which are also important parasites. Thus, as well as allowing the development of potential new drugs to treat nematode infections, our findings will serve as a starting point to investigate the similarities and differences between other 'versions' of trans-splicing.