An integrated strategy for control of animal and plant parasitic nematodes through targeting MOD-1

Nematodes are simple roundworms that share a similar worm-like shape yet range in size from the smallest microscopic species to a gigantic 3 metre long parasitic worm of sperm whale. They inhabit a correspondingly diverse range of habitats and include free-living and parasitic species. Free-living species are beneficial to the ecosystem. In contrast parasitic species cause major losses in food production and also 'neglected' human tropical diseases. The control of these nematodes is a particularly timely problem now for two reasons: The chemicals used to protect crops from plant parasitic nematodes are extremely toxic to users and the environment and are being withdrawn from use whilst at the same time drugs used to treat animal parasitic worm infections are losing their efficacy because nematodes are becoming resistant. Clearly, an approach is needed which will deliver chemicals that have low environmental impact and drugs that break resistance by acting in a completely new way. Arguably, the most successful nematicidal compounds to date have been those that have effects on the neuromuscular system of the worm. This means the worms can't move, feed or lay eggs and ultimately die. Of these, the most outstanding compound is ivermectin. Indeed, its discoverers won the Nobel Prize for the extraordinary benefit this compound has delivered to veterinary and human medicine. It revolutionised the treatment of human river blindness. An ivermectin-like chemical is also used in crop protection as a seed treatment. A key reason to the success of ivermectin is its selective toxicity i.e. it kills the parasite but has no detrimental effect on the mammalian host. It achieves this because it acts on a discrete signalling molecule, called a GluCl receptor that is only found in invertebrates. Therefore, the nematode worm has this receptor, and is killed by ivermectin, while the vertebrate mammalian host is unharmed. Unfortunately, due to more than three decades of use resistance to ivermectin has emerged and is a severe and increasing problem in the treatment of parasitic worms. Moreover, ivermectin kills a wide range of invertebrates including beneficial organisms and thus is not without environmental impact. We have found a new target that not only would deliver resistance-breaking chemicals but would also have lower toxicity to beneficial ecosystems. This target is the receptor MOD-1, first discovered in the nervous system of the nematode C. elegans that is widely used in laboratories around the world as a 'model' organism for parasitology. Importantly, activating the MOD-1 channel paralyses C. elegans showing that chemicals that target MOD-1 would be nematicidal. In addition, blocking MOD-1 disables plant parasitic nematodes and they can no longer enter roots. Notably, MOD-1 is largely restricted to the nematodes and is not widely found in insects e.g. in bees, and not at all in higher animals including mammals: This provides a compelling argument that chemicals that act on MOD-1 would have an excellent profile in terms of their selective toxicity. They could be deployed in veterinary medicine to kill the parasite whilst being well-tolerated by the animal receiving treatment and in crop protection to prevent plant disease but leave pollinating insects safe. The biology of this channel is intrinsically fascinating: We will characterise it using genetics, pharmacology and molecular modelling and in doing so find chemicals that interact with MOD-1. The latter will address the urgent need by both the agrochemical sector and the animal health sector for new environmentally friendly approaches to parasite control.