Seeking to ‘deliver’ benefits on fluke - Veterinary Practice
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Seeking to ‘deliver’ benefits on fluke

RICHARD GARD reports on developments in the battle against liver fluke

THE call is out for early action on liver fluke. EBLEX (English Beef and Lamb Executive) is alerting farmers that over 50% of cattle livers are being rejected at abattoirs and that Fasciola hepatica is already affecting large numbers of grazing cattle and sheep.

An early start to fluke treatment is advised as the wet weather has contributed to the expectation that acute clinical disease can be expected from now on. Because of the risk of residues, dairy cows are treated at drying off and regular tests of the bulk milk are advised to detect subclinical infection.

For anyone involved in the problems associated with liver fluke, the findings from the Design of Effective and Sustainable Control Strategies for Liver Fluke in Europe (DeLiver) will be of intense interest.

This initiative, involving 12 European and three South American research groups, has produced a CDRom providing advice for farmers and veterinarians, information for consumers and resources for students.

The aim is to provide the latest information and advice on combating liver fluke and there is a great deal of information on the website, together with contact points and download links.

Three main areas of concern are highlighted:

• Changing climate that better suits the parasite’s life-cycle and allows it to spread to new areas.

• Resistance to treatment with the widely used flukicide triclabendazole.

• The parasite’s ability to make animals more susceptible to other bacterial infections such as salmonellosis and bovine tuberculosis.

Down regulatory effect

If the link with bTB has drawn your attention, there is a paper yet to be inserted on the website from researchers at Dublin, Belfast and Copenhagen published in Transboundary and Emerging Diseases (2009) 56: 269- 274. The indications are that helminths induce a down regulatory effect that interferes with the immunological response to the tests for bTB. The significance of an increase in liver fluke in areas also struggling to control bTB may be highly significant. The contact point for the research is Grace.mulcahy

The grand design for the interlinking multidisciplinary projects is for the diagnosis and control of liver fluke by identifying risk factors, predictive forecasting, the use of drugs for treatment, parasitic resistance and the development of vaccines. One of the research groups is the Centre for Biocatalysis at Exeter University. The director, Professor Jenny Littlechild, and her associate, Dr Kirsty Line, patiently outlined aspects of molecular biology, protein biochemistry and macromolecular crystallography.

Lining the walls of the office area are “cartoons” of protein structures and Prof. Littlechild is an enthusiast of proteomics. Understanding the ways of proteins is deep science and one can only be impressed by the use of x-ray, a molecular biology laboratory, a protein biochemistry laboratory, bioinformatics and molecular graphics facilities.

Stop flow analysis for enzyme kinetics and other spectroscopic equipment contribute to the cartoons. A crystallisation robot and dynamic light scattering equipment are on the installation list.

In 2008, a paper from the Exeter group, in collaboration with workers from Oviedo, Spain, was published in Molecular and Biochemical Parasitology: The Fasciola hepatica thioredoxin: high resolution structure reveals two oxidative states.

It is likely that proteomics was not a subject for study for many veterinary surgeons but one can accept the significance that “this is the first example of a single crystal structure to show the active site cysteine residues in both the reduced and disulphide oxidised form.

Consistent with this observation the process of oxidation appears to require very little rearrangement of the surrounding protein structure.”

Key to understanding

Similarities between the thioredoxin protein structure for F. hepatica, human and animal hosts and the resemblance to other parasitic thioredoxins provide the key to understanding binding proteins and how the parasite resists drug treatments.

Much work has been carried out with fluke proteins to identify how these bind with triclabendazole. An understanding of the molecular basis of triclabendazole mechanism of action and resistance in liver fluke is leading to the structural identification of proteins that have been identified as vaccine candidates.

In some way, the thioredoxin Trx enzyme protects F. hepatica from reactive oxygen species including macrophages, neutrophils, eosinophils and platelets. It is the ability of the parasite to adapt and resist oxidative stress that allows the organism to continue to cause infection in the presence of the drug treatment.

Professor Littlechild identifies the need to “understand the target”. The fluke genome is to be sequenced. Early studies by collaborative groups with vaccinated cattle indicate that the fluke “displayed a reduced ability to hide from the cow’s immune system”.

Recognising drug failure

Resistance in the field is identified by recognition of drug failure. Improved tests for resistance (an egg hatch assay and copro-antigen ELISA) have been developed and a standardised field test to be used when resistance is suspected.

The Faecal Egg Count Reduction Test has been available for many years but the method has not been standardised and information on resistance is lacking.

Triclabendazole resistance has been identified in Ireland in a flock where closantel, oxyclozanide and nitrooxynil provided a 100% reduction in F. hepatica egg counts.

Under-dosing, frequent treatments and the use of the same drug repeatedly over a number of years are relevant factors to avoid if the only licensed drug with an efficacy against the very young stages of the migrating fluke, a major cause of acute disease in sheep, is to remain a treatment option.

The DeLiver website will offer an early warning forecasting system for fluke that will allow vets to advise on the timing of treatment. Whether this distinguishes between areas and counties may be important but the message is clear to plan ahead.

For anyone working in proteomics or related fields the biocatalysis group is hosting a conference on Novel Enzymes from 14th to 17th April 2010. Contact

Dr Kirsty Line will be working with the VLA from October so there may be further opportunities to apply the knowledge being developed about parasitic protein adaptation at field level.

Oxidative stress, suffered by the liver fluke, may become a point of discussion over the field gate.

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