ASCARIS SUUM, A NEW FUNCTIONAL GENOMICS PLATFORM FOR NEMATODE PARASITES

Nematodes (roundworms) are members of the Phylum Nematoda. There are >25,000 species of nematodes and they are outnumbered only by the Arthropods. Their success is due to their ability to occupy a diverse range of habitats. They can either be free-living or parasites of humans, animals and plants. Nematode parasites are a common source of human disease where 1 in 4 people carry at least one nematode species. Human parasitic diseases are mainly restricted to the developing world where poverty, inadequate health care provision, and poor living conditions favour their survival. Some of the most prevalent human nematode parasites live in the gasterointestinal (GI) system feeding on human tissue, blood and gut contents. For example, Ascaris lumbricoides is one of the largest GI nematodes and can cause serious health problems associated with intestinal blockage and impaired growth, especially in children. In livestock, nematode parasites can be a significant problem as they impact not only on the health and well-being of the animal but also on the productivity and subsequent profitability of the farming industry. Haemonchus contortus and Teladorsagia circumcincta are the most pathogenic nematodes of sheep and goats. They are blood-feeders and heavy infections can lead to severe anaemia and animal death. Nematodes are also problematic to the crop industry. They can infect food crops such as tomatoes and potatoes or utility grasses including football pitches or golf courses. Meloidogyne spp are a particular problem because they infect a wide range of plant hosts. They impair plant health by setting up feeding sites in the plant root, removing nutrients needed for plant growth.
Unfortunately the drugs that are available to treat parasitic nematode infections no longer work effectively or are environmentally toxic. We cannot continue to treat nematode infections with the current range of drugs and we must now actively seek new drug targets and develop novel drugs. This is particularly important to the UK as we have to ensure the sustainability of livestock farming for future food production.
This project aims to uncover novel drug targets for the treatment of nematode parasites of livestock. In this project we will collaborate with an animal-health pharmaceutical company to accelerate the chance of identifying a novel drug target at which new drugs could be directed. This approach will make use of scientific research skills and the expertise of the pharmaceutical industry in drug discovery. In order to find new drug targets for nematode parasites, we must first identify proteins that are important to nematode biology and survival. Recently there has been an increase in the availability of gene sequences for a number of important parasitic nematodes, like those described above. We will search through these sequences and find those which code for protein targets which may be essential to parasite survival. We will select sequences that are found in multiple parasites so that we can identify a drug target which could be used to treat multiple nematode diseases. We will then use a technique called RNA interference (RNAi) which allows us to switch off genes in the parasitic nematode to find out their function. For example, if we switch off a gene and the nematode dies or stops moving/feeding/reproducing then we have identified a good drug target candidate as the nematode can no longer infect or remain in its host. We will perform RNAi in a model nematode parasite (Ascaris suum) that we can easily collect from pig intestines at local abattoirs and maintain in the lab. Once we have switched off the target genes, we will determine the impact to the parasite by examining how they survive, behave, move, reproduce, and respond to stimulants. We will then select the five 'best' targets, based on their impact to nematode biology, and deliver these to the pharmaceutical industry who will develop drugs against them.

Nematode parasites impose a significant burden on human/animal health and global food security. The agricultural impact of nematodiasis in the UK is ~£80 million/year, mainly attributed to animal death, morbidity, reduced productivity and reproductive impairment. Traditionally chemotherapeutics have been the foundation of nematode parasite control, but decreasing utility / treatment failures have exposed the rapid development of drug resistance, including multi-drug resistance such that current control options are not sustainable. As a result, novel chemotherapeutics are critical. In this study we will employ both contemporary and traditional approaches to identify and validate novel drug target candidates for exploitation by our industrial partner. Our target-identification strategy will be directed by the recent progress in parasitic nematode genomics/ transcriptomics and will score targets based on their conservation across the phylum, known druggability in other systems, key role in nematode biology and/or survival, and expression in therapeutically relevant lifecycle stages/tissues. Our approaches to functional validation combine two unique attributes offered by this industrial-partnership collaboration: we will use our newly developed adult A. suum RNA interference (RNAi) platform to investigate target function/importance to parasite biology; uniquely, we will interface these reverse genetic approaches with privileged access to the Merial/Sanofi chemical library, which will provide powerful tools to help steer early target prioritisation and to probe functional importance. The combination of both of these tools will provide a powerful and unique approach to animal parasite drug target validation. These efforts will provide the first target validation platform for an animal parasitic nematode and will deliver five functionally-validated drug target candidates for industrial exploitation.

A. Commercial Private Sector
1. Pharma/Biotech will benefit through economic rewards associated with the provision of a new anthelmintic to a keen market. Our industrial partner (Merial) is committed to developing validated drug targets emerging from this project and exploiting these as screening tools for anthelmintic discovery. This project will also optimise a reverse genetics platform for validation of drug targets in nematode parasites, which will be available for exploitation by other pharma/biotech industries. Additional novel targets arising from this project, which are not of primary interest to Merial, will be available for validation by other industries. This is relevant to those developing treatments for both animal and human nematodiasis, and could provide opportunities for new jobs in the research/development/production pipeline.

2. Local and global farming enterprises will benefit through enhanced economic returns associated with healthier livestock that are more productive. The total income from farming in the UK was £4.7 billion in 2012 facilitating the employment of 481,000 personnel. On a global scale, nematode parasites are estimated to cost farmers $80 million / year. As a direct result of this project, livestock producers will receive economic gain through more effective drugs that are free from resistance. Novel anthelmintics will permit reduced drug treatments, and will enhance animal health, welfare and productivity. Increased productivity will drive economic success in all businesses involved in the 'farm to fork' production process, bolstering the competitiveness of the UK Agri-Food Industry.

B. Policy Makers
1. Stakeholders and policy makers will benefit through research-evidence that will inform policy development:: UK-based government bodies (DEFRA, DARD), Levy boards (EBLEX, BPEX), and other representatives of the Agri-Food industry will benefit as this project will provide an evidence-base for policy development and addresses EU-directed changes in agricultural legislation, e.g. the need for rapid drug-intervention to facilitate 'Sustainable Intensification'.

C. Public Sector
1. Farming communities in developing countries will benefit through enhanced quality of life: Nematode parasites have a devastating impact on agriculture in developing countries where many farmers and their families rely on livestock for income and food. Further, they infect >1/4 of the world's population causing serious morbidity. The goal of this project is the development of novel drugs for the treatment of nematode pathogens in livestock, which has the potential to improve quality of life through enhanced economic gain. Moreover the development of novel drugs for veterinary parasites which can be repurposed for use in humans will improve the health, well-being, and quality of life of those afflicted with nematodiasis.

2. Educational sector will benefit through greater understanding of the local and global significance of nematode pathogens: Local schools will benefit from this research by educating students and teachers about nematode biology, and through raised awareness of the importance of research in our society. In addition, research findings will form the basis of research-led teaching to university students at QUB. The host-institute will benefit through an enhanced research profile.

3. General public will benefit through job-creation and opportunity to promote sustainable prosperity: There is a growing demand from the consumer for organic and chemical residue-reduced food that is produced cost-effectively from animals maintained in a welfare-friendly environment. A novel, resistance-free anthelmintic will facilitate a reduction in drug use, therefore limiting food contamination and facilitating the organic farmer who is restricted to reduced treatment regimes. Also, the environmental impact associated with intensive drug use will be reduced.