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      Refugia and anthelmintic resistance: Concepts and challenges

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          Abstract

          Anthelmintic resistance is a threat to global food security. In order to alleviate the selection pressure for resistance and maintain drug efficacy, management strategies increasingly aim to preserve a proportion of the parasite population in ‘refugia’, unexposed to treatment. While persuasive in its logic, and widely advocated as best practice, evidence for the ability of refugia-based approaches to slow the development of drug resistance in parasitic helminths is currently limited. Moreover, the conditions needed for refugia to work, or how transferable those are between parasite-host systems, are not known. This review, born of an international workshop, seeks to deconstruct the concept of refugia and examine its assumptions and applicability in different situations. We conclude that factors potentially important to refugia, such as the fitness cost of drug resistance, the degree of mixing between parasite sub-populations selected through treatment or not, and the impact of parasite life-history, genetics and environment on the population dynamics of resistance, vary widely between systems. The success of attempts to generate refugia to limit anthelmintic drug resistance are therefore likely to be highly dependent on the system in hand. Additional research is needed on the concept of refugia and the underlying principles for its application across systems, as well as empirical studies within systems that prove and optimise its usefulness.

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          Highlights

          • Refugia is currently recommended for strategic control of AR in GI nematodes of livestock.

          • Conditions required for refugia-based control may differ between parasite systems.

          • An improved understanding of the parameters influencing refugia-based control is required.

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          Most cited references62

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          Regulation and Stability of Host-Parasite Population Interactions: I. Regulatory Processes

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            Parallel compensatory evolution stabilizes plasmids across the parasitism-mutualism continuum.

            Plasmids drive genomic diversity in bacteria via horizontal gene transfer [1, 2]; nevertheless, explaining their survival in bacterial populations is challenging [3]. Theory predicts that irrespective of their net fitness effects, plasmids should be lost: when parasitic (costs outweigh benefits), plasmids should decline due to purifying selection [4-6], yet under mutualism (benefits outweigh costs), selection favors the capture of beneficial accessory genes by the chromosome and loss of the costly plasmid backbone [4]. While compensatory evolution can enhance plasmid stability within populations [7-15], the propensity for this to occur across the parasitism-mutualism continuum is unknown. We experimentally evolved Pseudomonas fluorescens and its mercury resistance mega-plasmid, pQBR103 [16], across an environment-mediated parasitism-mutualism continuum. Compensatory evolution stabilized plasmids by rapidly ameliorating the cost of plasmid carriage in all environments. Genomic analysis revealed that, in both parasitic and mutualistic treatments, evolution repeatedly targeted the gacA/gacS bacterial two-component global regulatory system while leaving the plasmid sequence intact. Deletion of either gacA or gacS was sufficient to completely ameliorate the cost of plasmid carriage. Mutation of gacA/gacS downregulated the expression of ∼17% of chromosomal and plasmid genes and appears to have relieved the translational demand imposed by the plasmid. Chromosomal capture of mercury resistance accompanied by plasmid loss occurred throughout the experiment but very rarely invaded to high frequency, suggesting that rapid compensatory evolution can limit this process. Compensatory evolution can explain the widespread occurrence of plasmids and allows bacteria to retain horizontally acquired plasmids even in environments where their accessory genes are not immediately useful.
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              Current Threat of Triclabendazole Resistance in Fasciola hepatica.

              Triclabendazole (TCBZ) is the only chemical that kills early immature and adult Fasciola hepatica (liver fluke) but widespread resistance to the drug greatly compromises fluke control in livestock and humans. The mode of action of TCBZ and mechanism(s) underlying parasite resistance to the drug are not known. Due to the high prevalence of TCBZ resistance (TCBZ-R), effective management of drug resistance is now critical for sustainable livestock production. Here, we discuss the current status of TCBZ-R in F. hepatica, the global distribution of resistance observed in livestock, the possible mechanism(s) of drug action, the proposed mechanisms and genetic basis of resistance, and the prospects for future control of liver fluke infections using an integrated parasite management (IPM) approach.
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                Author and article information

                Contributors
                Journal
                Int J Parasitol Drugs Drug Resist
                Int J Parasitol Drugs Drug Resist
                International Journal for Parasitology: Drugs and Drug Resistance
                Elsevier
                2211-3207
                17 May 2019
                August 2019
                17 May 2019
                : 10
                : 51-57
                Affiliations
                [a ]Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7ZJ, UK
                [b ]Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA
                [c ]Moredun Research Institute, Pentlands Science Park, Edinburgh, EH26 0PZ, UK
                [d ]School of Biological Sciences, Queen's University Belfast, Chlorine Gardens, Belfast, BT9 5BL, UK
                [e ]Odum School of Ecology, University of Georgia, Athens, GA, 30602, USA
                [f ]Institute of Integrative Biology, University of Liverpool, L69 7ZB, UK
                [g ]Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, G61 1QH, UK
                [h ]Royal (Dick) School of Veterinary Studies, Easter Bush Veterinary Centre, Roslin, EH25 9RG, UK
                [i ]Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK
                [j ]SRUC, Peter Wilson Building, West Mains Road, Edinburgh, EH9 3JG, UK
                Author notes
                []Corresponding author. eileen.devaney@ 123456glasgow.ac.uk
                Article
                S2211-3207(19)30050-8
                10.1016/j.ijpddr.2019.05.001
                6531808
                31125837
                2a4e296c-e659-4de3-a32f-2ef32161b90f
                © 2019 Published by Elsevier Ltd on behalf of Australian Society for Parasitology.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 March 2019
                : 10 May 2019
                : 12 May 2019
                Categories
                Article

                refugia,anthelmintic drug,resistance,parasite,control,fitness
                refugia, anthelmintic drug, resistance, parasite, control, fitness

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