Moulting and hatching in nematodes; the role of astacin metalloproteases as potential anti-nematode targets

Parasitic nematodes are a major pest of plants and animals. Around 1 billion people, predominantly in the developing world, harbour parasitic nematodes that cause chronic and debilitating diseases. In addition, nematodes cause a significant economic burden to agriculture, affecting crops and livestock throughout the world. Methods to control nematodes are relatively limited, and drug resistance is becoming common. All nematodes share a common lifecycle growing from an egg through 4 immature larval stages before reaching the sexually mature adult stage. Progression from egg to larvae involves a hatching process, and from individual larval stages to adulthood involves a repeated process termed moulting, where the external skeleton is shed and a new one synthesised. The moulting process allows growth. The astacin enzymes are catalysts that are involved in the processes of hatching, skeleton synthesis and moulting. The specific roles played by this class of enzymes have been confirmed in a model experimental system and will now be examined and characterized in an important veterinary parasite. The nematode Haemonchus contortus is a common and economically significant parasite of sheep and goats. Information gained in this system will also be of relevance in other parasites of animals and plants. The project aims are to identify, study and exploit these enzymes with the overall goal of identifying vaccine and drug targets to treat and control nematode infections.

Parasitic nematodes infect man, his domestic animal and crops and represent a significant medical, veterinary and agricultural burden. Trichostrongylid infections of livestock are widespread causing morbidity, death and economic losses. Effective antihelminthic drugs are limited and multiple resistance is emerging thus highlighting the need to identify novel targets and new means of nematode control. All nematodes undergo a set developmental pathway from the egg through 4 larval stages before reaching the sexually mature adult stage. Progression from embryo to larvae involves a hatching process, and from individual larval stages to adulthood involves a repeated process termed moulting, where the collagenous cuticle is shed and a new one synthesised. The astacin class of enzymes are key players in the nematode-specific processes of hatching, exoskeleton synthesis and moulting. The specific roles played by the nematode-specific subclass V astacins have been confirmed in the Caenorhabditis elegans model experimental system and will now be examined in the veterinary parasite Haemonchus contortus. This project will identify and functionally characterize the H. contortus class V astacins. Information gained in this system will be of relevance in other nematode parasites of animals and plants, and will be aimed at characterizing and exploiting these enzymes with the overall goal of identifying vaccine and drug targets to treat and control nematode infections.