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Molecular Knowledge of Mechanisms of Helminth Resistance: Importance for Diagnostic and Epidemiology

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Abstract

Helminths infestations in animals and humans are mostly controlled by anthelmintics. Large-scale treatment has led to resistance to many drugs, namely benzimidazoles, avermectins and levamisole. Whereas avermectins and levamisole resistance appear to be multigenic, benzimidazole resistance is largely monogenic, based on polymorphism in β-tubulin gene. Spatial distribution of β-tubulin alleles in closed helminths populations supports a common origin of alleles on a specific farm. The main forces responsible for anthelmintic resistance development in field populations are the introduction of ancestral alleles (i.e. pre existing polymorphism in helminths before herds’ constitution) and the selection of alleles appeared after herds’ constitution. The acquisition of resistance may have a cost that counterbalance the advantage of being resistant. For benzimidazole resistance, the interaction between life-traits combining advantages and disadvantages for resistant genotypes, compared to susceptible ones, may explain the stability of acquired resistance along years. Much remains to be done for avermectins and levamisole resistance, for which molecular mechanisms remain to be identified.

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References

  • Alvarez L, Lifschitz A, Entrocasso C et al (2008) Evaluation of the interaction between ivermectin and albendazole following their combined use in lambs. J Vet Pharmacol Ther 31:230–239

    Article  PubMed  CAS  Google Scholar 

  • Bartley DJ, Jackson F, Jackson E et al (2004) Characterisation of two triple resistant field isolates of Teladorsagia from Scottish lowland sheep farms. Vet Parasitol 123:189–199

    Article  PubMed  CAS  Google Scholar 

  • Beech RN, Silvestre A (2010) Mutations associated with anthelmintic drug resistance. Anti-Infect Agents Med Chem 9:105–112

    CAS  Google Scholar 

  • Beech RN, Prichard RK, Scott ME (1994) Genetic variability of the beta-tubulin genes in benzimidazole-susceptible and -resistant strains of Haemonchus contortus. Genetics 138:103–110

    PubMed  CAS  Google Scholar 

  • Besier B, Knox M, Love S (2003) Individual sheep management – new opportunities for objective parasite control. Wool Tech Sheep Breed 51:146–147

    Google Scholar 

  • Blouin MS, Yowell CA, Courtney CH et al (1995) Host movement and the genetic structure of populations of parasitic nematodes. Genetics 141:1007–1014

    PubMed  CAS  Google Scholar 

  • Boulin T, Gielen M, Richmond JE et al (2008) Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor. Proc Natl Acad Sci USA 105:18590–18595

    Article  PubMed  CAS  Google Scholar 

  • Bourguinat C, Ardelli BF, Pion SDS et al (2008) P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus. Mol Biochem Parasitol 158:101–111

    Article  PubMed  CAS  Google Scholar 

  • Cabaret J (2010) False resistance to antiparasitic drugs: causes from shelf availability to patient compliance. Anti-Infect Agents Med Chem 9:161–167

    CAS  Google Scholar 

  • Coles GC (2002) Cattle nematodes resistant to anthelmintics: why so few cases? Vet Res 33:481–489

    Article  PubMed  CAS  Google Scholar 

  • Cully DF, Paress PS (1991) Solubilization and characterization of a high affinity ivermectin binding site from Caenorhabditis elegans. Mol Pharmacol 40:326–332

    PubMed  CAS  Google Scholar 

  • Cully DF, Vassilatis DK, Liu KK et al (1994) Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371:707–711

    Article  PubMed  CAS  Google Scholar 

  • Dent JA, Smith MM, Vassilatis DK et al (2000) The genetics of ivermectin resistance in Caenorhabditis elegans. Proc Natl Acad Sci USA 97:2674–2679

    Article  PubMed  CAS  Google Scholar 

  • Elard L (1998) La résistance aux benzimidazoles chez Teladorsagia circumcincta, nématode parasite de petits ruminants Etude du déterminisme génétique et recherche des conséquences sur la fitness des parasites Université François Rabelais, Tours

    Google Scholar 

  • Elard L, Humbert JF (1999) Importance of the mutation of amino acid 200 of the isotype 1 beta-tubulin gene in the benzimidazole resistance of the small-ruminant parasite Teladorsagia circumcincta. Parasitol Res 85:452–456

    Article  PubMed  CAS  Google Scholar 

  • Elard L, Comes AM, Humbert JF (1996) Sequences of beta-tubulin cDNA from benzimidazole-susceptible and -resistant strains of Teladorsagia circumcincta, a nematode parasite of small ruminants. Mol Biochem Parasitol 79:249–253

    Article  PubMed  CAS  Google Scholar 

  • Elard L, Sauve C, Humbert JF (1998) Fitness of benzimidazole-resistant and -susceptible worms of Teladorsagia circumcincta, a nematode parasite of small ruminants. Parasitology 117:571–578

    Article  PubMed  Google Scholar 

  • Eng JKL, Blackhall WJ, Osei-Atweneboana MY, Bourguinat C, Galazzo D, Beech RN, Unnasch TR, Awadzi K, Lubega GW, Prichard RK (2006) Ivermectin selection on betatubulin: evidence in Onchocerca volvulus and Haemonchus contortus. Mol Biochem Parasitol 150:229–235

    Google Scholar 

  • Enyati A, Hemingway J (2010) Malaria management: past, present and future. Annu Rev Entomol 55:569–591

    Article  Google Scholar 

  • Fleming JT, Squire MD, Barnes TM et al (1997) Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits. J Neurosci 17:5843–5857

    PubMed  CAS  Google Scholar 

  • Geary TG, Sims SM, Thomas EM et al (1993) Haemonchus contortus: ivermectin-induced paralysis of the pharynx. Exp Parasitol 77:88–96

    Article  PubMed  CAS  Google Scholar 

  • Gilleard JS, Beech RN (2007) Population genetics of anthelmintic resistance in parasitic nematodes. Parasitology 134:1133–1147

    Article  PubMed  CAS  Google Scholar 

  • Grillo V, Jackson F, Gilleard JS (2006) Characterisation of Teladorsagia circumcincta microsatellites and their development as population genetic markers. Mol Biochem Parasitol 148:181–189

    Article  PubMed  CAS  Google Scholar 

  • Hoekstra R, Criado-Fornelio A, Fakkeldij J et al (1997) Microsatellites of the parasitic nematode Haemonchus contortus: polymorphism and linkage with a direct repeat. Mol Biochem Parasitol 89:97–107

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Xiao SH, Aroian RV (2009) The new anthelmintic tribendimidine is an L-type (levamisole and pyrantel) nicotinic acetylcholine receptor agonist. Plos Negl Trop Dis. doi:10.1371/journal.pntd.0000499

    Google Scholar 

  • Huson DH (1998) SplitsTree: analyzing and visualizing evolutionary data. Bioinformatics 14:68–73

    Article  PubMed  CAS  Google Scholar 

  • Jones AK, Buckingham SD, Sattelle DB (2005) Chemistry-to-gene screens in Caenorhabditis elegans. Nat Rev Drug Discov 4:321–330

    Article  PubMed  CAS  Google Scholar 

  • Kaminsky R, Ducray P, Jung M (2008) A new class of anthelmintics effective against drug-resistant nematodes. Nature 452:176–180

    Article  PubMed  CAS  Google Scholar 

  • Kaplan RM (2004) Drug resistance in nematodes of veterinary importance: a status report. Trends Parasitol 20:477–481

    Article  PubMed  CAS  Google Scholar 

  • Kerboeuf D, Guegnard F, Le Vern Y (2003) Detection of P-glycoprotein-mediated multidrug resistance against anthelmintics in Haemonchus contortus using anti-human mdr1 monoclonal antibodies. Parasitol Res 91:79–85

    Article  PubMed  CAS  Google Scholar 

  • Kerboeuf D, Riou M, Neveu C et al (2010) Membrane drug transport in helminths. Anti-Infect Agents in Med Chem 9:113–129

    CAS  Google Scholar 

  • Kopp SR, Coleman GT, Traub RJ et al (2009) Acetylcholine receptor subunit genes from Ancylostoma caninum: altered transcription patterns associated with pyrantel resistance. Int J Parasitol 39:435–441

    Article  PubMed  CAS  Google Scholar 

  • Kwa MSG, Veenstra JG, Roos MH (1994) Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in beta-tubulin isotype 1. Mol Biochem Parasitol 63:299–303

    Article  PubMed  CAS  Google Scholar 

  • Kwa MSG, Veenstra JG, Dijk MV et al (1995) Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. J Mol Biol 246:500–510

    Article  PubMed  CAS  Google Scholar 

  • Lacey E, Prichard RK (1986) Interactions of benzimidazoles (BZ) with tubulin from BZ-sensitive and BZ-resistant isolates of Haemonchus contortus. Mol Biochem Parasitol 19:171–181

    Article  PubMed  CAS  Google Scholar 

  • Lawrence KE, Rhodes AP, Jackson R et al (2006) Farm management practices associated with macrocyclic lactone resistance on sheep farms in New Zealand. N Z Vet J 54:283–288

    Article  PubMed  CAS  Google Scholar 

  • Leignel V, Cabaret J (2001) Massive use of chemotherapy influences life traits of parasitic nematodes in domestic ruminants. Funct Ecol 15:569–574

    Article  Google Scholar 

  • Leignel V, Humbert JF (2001) Mitochondrial DNA variation in benzimidazole-resistant and -susceptible populations of the small ruminant parasite, Teladorsagia circumcincta. J Hered 92:503–506

    Article  PubMed  CAS  Google Scholar 

  • Leignel V, Cabaret J, Humbert JF (2002) New molecular evidence that Teladorsagia circumcincta (Nematoda: Trichostrongylidea) is a species complex. J Parasitol 88:135–140

    PubMed  CAS  Google Scholar 

  • Leignel V, Silvestre A, Humbert JF, Cabaret J (2010) Alternation of anthelmintic treatments: a molecular evaluation for benzimidazole resistance in nematodes. Vet Parasitol 172:80–88

    Article  PubMed  CAS  Google Scholar 

  • Martin RJ, Robertson AP (2007) Mode of action of levamisole and pyrantel, Anthelmintic Resistance, E153 and Q57. Parasitology 134:1093–1104

    Article  PubMed  CAS  Google Scholar 

  • McCavera S, Rogers AT, Yates DM et al (2009) An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus. Mol Pharmacol 75:1347–1355

    Article  PubMed  CAS  Google Scholar 

  • Melo AC (2005) Resistance to benzimidazoles in nematoda Haemonchus contortus in Ceara state. PhD thesis, Fortaleza University, Ceara, Brazil, 170 pp

    Google Scholar 

  • Molento MB, Prichard RK (1999) Effects of the multidrug-resistance-reversing agents verapamil and CL 347,099 on the efficacy of ivermectin or moxidectin against unselected and drug-selected strains of Haemonchus contortus in jirds (Meriones unguiculatus). Parasitol Res 85:1007–1011

    Article  PubMed  CAS  Google Scholar 

  • Mottier MD, Prichard RK (2008) Genetic analysis of a relationship between macrocyclic lactone and benzimidazole anthelmintic selection on Haemonchus contortus. Pharmacogenet Genom 18:129–140

    Article  CAS  Google Scholar 

  • Neveu C, Charvet C, Fauvin A et al (2007) Identification of levamisole resistance markers in the parasitic nematode Haemonchus contortus using a cDNA-AFLP approach. Parasitology 134:1105–1110

    Article  PubMed  CAS  Google Scholar 

  • Neveu C, Charvet C, Fauvin A et al (2010) Genetic diversity of levamisole receptor subunits in parasitic nematode species and abbreviated transcripts associated with resistance. Pharmacogenet Genom 20:414–425

    CAS  Google Scholar 

  • Njue AI, Prichard RK (2004) Genetic variability of glutamate-gated chloride channel genes in ivermectin-susceptible and -resistant strains of Cooperia oncophora. Parasitology 129:741–751

    Article  PubMed  CAS  Google Scholar 

  • Otsen M, Plas ME, Lenstra JA et al (2000) Microsatellite diversity of isolates of the parasitic nematode Haemonchus contortus. Mol Biochem Parasitol 110:69–77

    Article  PubMed  CAS  Google Scholar 

  • Palcy C, Silvestre A, Sauve C et al (2010) Benzimidazole resistance in Trichostrongylus axei in sheep: long-term monitoring of affected sheep and genotypic evaluation of the parasite. Vet J 183:68–74

    Article  PubMed  CAS  Google Scholar 

  • Pion SDS, Nana-Djeunga H, Bourguinat C et al (2009) Dynamics of Onchocerca volvulus microfilarial loads of cameroonian patients submitted to repeated (5–23) ivermectin treatments over 14 years (1994–2007). Am J Trop Med Hyg 79:339

    Google Scholar 

  • Pomroy WE (2006) Anthelmintic resistance in New Zealand: a perspective on recent findings and options for the future. N Z Vet J 54:265–270

    Article  PubMed  CAS  Google Scholar 

  • Prichard RK, Roulet A (2007) ABC transporters and beta-tubulin in macrocyclic lactone resistance: prospects for marker development. Parasitology 134:1123–1132

    Article  PubMed  CAS  Google Scholar 

  • Prichard RK, Oxberry M, Bounhas Y et al (2000) Polymerisation and benzimidazole binding assays with recombinant a- and b-tubulins from Haemonchus contortus In: American association of veterinary parasitologists, 45th annual meeting, Salt Lake City Marriott, p 81

    Google Scholar 

  • Riley LW (2004) Molecular epidemiology of infectious diseases: principles and practices. ASM Press, Washington, DC, 1752 N st NW

    Google Scholar 

  • Robertson SJ, Martin RJ (1993) Levamisole-activated single-channel currents from muscle of the nematode parasite Ascaris-suum. Br J Pharmacol 108:170–178

    PubMed  CAS  Google Scholar 

  • Robertson AP, Bjorn HE, Martin RJ (1999) Resistance to levamisole resolved at the single-channel level. FASEB J 13:749–760

    PubMed  CAS  Google Scholar 

  • Rufener L, Kaminsky R, Maser P (2009) In vitro selection of Haemonchus contortus for benzimidazole resistance reveals a mutation at amino acid 198 of beta-tubulin. Mol Biochem Parasitol 168:120–122

    Article  PubMed  CAS  Google Scholar 

  • Sangster NC, Riley FL, Wiley LJ (1998) Binding of [3 H]m-aminolevamisole to receptors in levamisole-susceptible and -resistant Haemonchus contortus. Int J Parasitol 28:707–717

    Article  PubMed  CAS  Google Scholar 

  • Sargison ND, Jackson F, Bartley DJ et al (2007) Observations on the emergence of multiple anthelmintic resistance in sheep flocks in the south-east of Scotland. Vet Parasitol 145:65–76

    Article  PubMed  CAS  Google Scholar 

  • Shayan P, Eslami A, Borji H (2007) Innovative restriction site created PCR-RFLP for detection of benzimidazole resistance in Teladorsagia circumcincta. Parasitol Res 100:1063–1068

    Article  PubMed  Google Scholar 

  • Silvestre A, Cabaret J (2002) Mutation in position 167 of isotype 1 beta-tubulin gene of Trichostrongylid nematodes: role in benzimidazole resistance. Mol Biochem Parasitol 120:297–300

    Article  PubMed  CAS  Google Scholar 

  • Silvestre A, Humbert JF (2000) A molecular tool for species identification and benzimidazole resistance diagnosis in larval communities of small ruminant parasites. Exp Parasitol 95:271–276

    Article  PubMed  CAS  Google Scholar 

  • Silvestre A, Humbert JF (2002) Diversity of benzimidazole-resistance alleles in populations of small ruminant parasites. Int J Parasitol 32:921–928

    Article  PubMed  CAS  Google Scholar 

  • Silvestre A, Leignel V, Berrag B et al (2002) Sheep and goat nematode resistance to anthelmintics: pro and cons among breeding management factors. Vet Res 33:465–480

    Article  PubMed  CAS  Google Scholar 

  • Silvestre A, Sauve C, Cortet J et al (2009) Contrasting genetic structures of two parasitic nematodes, determined on the basis of neutral microsatellite markers and selected anthelmintic resistance markers. Mol Ecol 18:5086–5100

    Article  PubMed  CAS  Google Scholar 

  • Taly A, Corringer PJ, Guedin D et al (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 8:733–750

    Article  PubMed  CAS  Google Scholar 

  • Tiwari J, Kumar S, Kolte AP et al (2006) Detection of benzimidazole resistance in Haemonchus contortus using RFLP-PCR technique. Vet Parasitol 138:301–307

    Article  PubMed  CAS  Google Scholar 

  • Towers PR, Edwards B, Richmond JE (2005) The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor alpha subunit. J Neurochem 93:1–9

    Article  PubMed  CAS  Google Scholar 

  • Vermunt JJ, West DM, Pomroy WE (1995) Multiple resistance to ivermectin and oxfendazole in Cooperia species of cattle in New Zealand. Vet Rec 137:43–45

    Article  PubMed  CAS  Google Scholar 

  • von Samson-Himmelstjerna G, Walsh TK, Donnan AA et al (2009) Molecular detection of benzimidazole resistance in Haemonchus contortus using real-time PCR and pyrosequencing. Parasitology 136:349–358

    Article  Google Scholar 

  • Walsh TK, Donnan AA, Jackson F et al (2007) Detection and measurement of benzimidazole resistance alleles in Haemonchus contortus using real-time PCR with locked nucleic acid Taqman probes. Vet Parasitol 144:304–312

    Article  PubMed  CAS  Google Scholar 

  • William S, Sabra A, Ramzy F et al (2001) Stability and reproductive fitness of Schistosoma mansoni isolates with decreased sensitivity to praziquantel. Int J Parasitol 31:1093–1100

    Article  PubMed  CAS  Google Scholar 

  • Williamson SM, Robertson AP, Brown L et al (2009) The nicotinic acetylcholine receptors of the parasitic nematode Ascaris suum: formation of two distinct drug targets by varying the relative expression levels of two subunits. PLoS Pathog. doi:10.1371/journal.ppat.1000517

    Google Scholar 

  • Wolstenholme AJ, Fairweather I, Prichard R, von Samson-Himmelstjerna G, Sangster NC (2004) Drug resistance in veterinary helminths. Trends Parasitol 20:469–476

    Google Scholar 

  • Xu M, Molento M, Blackhall W et al (1998) Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog. Mol Biochem Parasitol 91:327–335

    Article  PubMed  CAS  Google Scholar 

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Silvestre, A., Cabaret, J. (2012). Molecular Knowledge of Mechanisms of Helminth Resistance: Importance for Diagnostic and Epidemiology. In: Morand, S., Beaudeau, F., Cabaret, J. (eds) New Frontiers of Molecular Epidemiology of Infectious Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2114-2_11

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