Beyond the Connectome: Unravelling Neuropeptide Signalling in Parasitic Nematodes to Inform Drug Discovery Pipelines

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Nematodes, or roundworms, are highly successful invertebrates. There are >25,000 species which can be either free-living or parasites of humans, animals and plants, acting as a common source of disease. Human parasites are particularly prevalent in less economically developed countries where poverty, inadequate healthcare provision, and poor living conditions are commonplace and favour nematode persistence. Many human parasitic nematodes live in the gastrointestinal system, lymphatic system, or body tissues, where they cause serious health problems to the host. Infections in children impact on their physical and intellectual development, while nematode disease in adults can result in an inability to work and provide for their families. Globally, nematode infections are also common in agricultural livestock negatively impacting animal productivity (including meat and milk production) and the subsequent economic sustainability of the UK agri-food industry.Unfortunately, the drugs currently available to treat parasitic nematode infections (anthelmintics) no longer work effectively. Indeed, anthelmintic resistance in nematode parasites is a major local and global problem. In some areas of the world (for example, Scotland and New Zealand), sheep and cattle cannot be farmed due to nematode parasite control problems. Therefore, the development of new drugs to treat such resistant nematode parasites is urgently needed both in the UK and globally. New drugs are critical to the long-term sustainability of livestock farming for future food production.The nematode nerve-muscle system (neuromuscular system) is a proven source of drug targets. Indeed, the majority of anthelmintic drugs used to control nematode infectionhave exerted their effects on this system. The neuromuscular system of nematodes coordinates behaviour, controlling vital processes such as movement, feeding and reproduction. If these processes can be effectively interrupted then nematode parasite survival and transmission will be significantly reduced. The neuromuscular system continues to receive attention from academics and pharmaceutical companies searching for new drug targets. Indeed the neuromuscular system in nematodes is currently underexploited as a drug target source, with many novel resistance-breaking targets awaiting discovery. In order to develop new drugs that target the neuromuscular system of parasites we need a better understanding of the nematode nervous system structure and function. The nematode nervous system is complex and our current knowledge on its structure is based on a free-living model nematode called Caenorhabditis elegans. We have a detailed map of every single nerve cell (neuron) in C. elegans and all of the connections between them. We call this the connectome. However, we do not know anything about the communication that can occur outside of the connectome, via the fluid-filled body cavity. This is important as signalling beyond the connectome (extrasynaptic signalling via the body cavity fluid) is believed to be a key part of the communication system in nematodes, and yet we know very little about it. A more comprehensive understanding of nematode extrasynaptic signalling will enable us to better exploit the neuromuscular system as a drug target resource. This project uses a variety of sophisticated technologies and tools to investigate the extent and significance of extrasynaptic signalling in nematodes, by exploiting the large gastrointestinal nematode parasite, Ascaris suum, as a model system. The size of Ascaris allows us to easily collect its body cavity fluid and analyse the signalling molecules it contains - this has not been done before and would be very difficult in other nematode species. The information generated from this project will help us to better understand nematode biology and will provide valuable data for drug discovery by the pharmaceutical industry.