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Tools to identify new antiparasitic drugs for livestock

Preserving the efficacy of antiparasitic treatments and discovering new active compounds is a crucial challenge for human and animal health. With support from the ICSA Carnot Institute (now France Futur Élevage), new perspectives are opening in understanding and developing anthelminthic treatments.

Larve infestante de nématode protostrongle, extraite d'un escargot.. © INRA, CABARET Jacques

Gastrointestinal nematodes are parasitic worms that can be found in both animals and humans. Very widespread in developing countries, they can cause delayed growth and development in children and malnutrition in adults. In farmed livestock, these cosmopolitan parasites are particularly present in ruminants and give rise to reduced zootechnical performance, causing major economic losses.

There is no vaccine against these parasites and only anthelminthic treatments can effectively control the worms.

In the absence of alternative strategies such as vaccination, their control is mainly reliant on broad-spectrum anthelmintic treatments. However, their efficacy is now largely compromised by resistant worms, particularly in the livestock industry.. Nevertheless, anthelminthics belonging to the family of cholinergic agonists remain the most effective. These compounds target  acetylcholine receptors  . They cause prolonged stimulation of the receptors (agonist compounds), leading to uninterrupted contractions (spasms) of the nematode's muscles. The worms then become unable to maintain their presence in the host and are voided. Understanding the functioning of these receptors is of strategic importance when developing new and sustainable strategies to control these parasites.

Actions by the ICSA Carnot Institute

With the support of ICSA, scientists in the “Multi-resistance and pathogenic potential of nematodes” (MPN) team in the Joint Research Unit for Infectiology and Public Health at the INRA Centre in Tours mobilised their forces to propose an ambitious project to study the diversity of parasitic nematode acetylcholine receptors.

In vitro creation of acetylcholine receptors in nematodes

These receptors may be extremely varied. They are pentamers made up of five transmembrane sub-units that are of considerable diversity; indeed, some species of parasitic worms contain more than thirty different sub-units. By developing a heterologous system for the expression of cholinergic receptors in parasites, the scientists have been able to recreate the receptors in vitro (in the oocytes of the aquatic frog Xenopus laevis), by varying the number and composition of the sub-units in combination with certain auxiliary proteins.

This system is thus able to create receptors whose pharmacological properties correspond to those observed in vivo in the parasite. To date, the scientists have characterised several acetylcholine receptors that are susceptible to anthelminthics (levamisole, pyrantel, morantel, tribendimine, derquantel and nicotine), thus demonstrating the influence of the receptor's composition on its pharmacological properties. A new type of cholinergic receptor (called M-AChR) has also been characterised in sheep and equine parasites of importance to animal health (H. contortus and P. equorum). It has been shown that these receptors are present in the species most pathogenic to animals – and to humans – but are absent from free-living soil nematodes and species that are plant parasites. These receptors constitute major targets for the development of new and more selective anthelminthic agents that are also more environmentally-friendly.  
At present, research on these cholinergic receptors is ongoing and extending to other animal species (such as ticks and lice). This work should open the way towards the development of novel therapeutic solutions that could be implemented in the context of collaborative projects with interested companies.

For more information

  • Courtot, E., Charvet, C. L., Beech, R. N., Harmache, A., Wolstenholme, A. J., Holden-Dye, L., ... & Neveu, C. (2015). Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes. PLoS Pathog, 11(12), e1005267.
  • Boulin, T., Fauvin, A., Charvet, C. L., Cortet, J., Cabaret, J., Bessereau, J. L., & Neveu, C. (2011). Functional reconstitution of Haemonchus contortus acetylcholine receptors in Xenopus oocytes provides mechanistic insights into levamisole resistance. British journal of pharmacology, 164(5), 1421-1432.
  • Buxton, S. K., Charvet, C. L., Neveu, C., Cabaret, J., Cortet, J., Peineau, N., ... & Martin, R. J. (2014). Investigation of acetylcholine receptor diversity in a nematode parasite leads to characterization of tribendimidine-and derquantel-sensitive nAChRs. PLoS Pathog, 10(1), e1003870.

For more information on the ICSA Carnot Institute (now France Futur Élevage)

Because of its scientific excellence and know-how relative to partnerships with the private sector, the Joint Research Unit for Infectiology and Public Health was one of the sixteen research units selected to form the Animal Health Carnot Institute, or ICSA. Because the aim of this network was to develop public/private partnership research in response to the major challenges faced in animal health, the good contract negotiation practices of ICSA enabled it to facilitate and accelerate links between the research unit and companies, in the context of work protected by confidentiality.
NB – In 2016 the Animal Health Carnot Institute (ICSA) became the France Futur Élevage Carnot Institute.
http://www.ic-sante-animale.com/fr/