Skip to main content Accessibility help
×
Home

Single nucleotide polymorphism (SNP) markers for benzimidazole resistance in veterinary nematodes

  • G. VON SAMSON-HIMMELSTJERNA (a1), W. J. BLACKHALL (a1), J. S. McCARTHY (a2) and P. J. SKUCE (a3)

Summary

Resistance to the benzimidazole class of anthelmintics in nematodes of veterinary importance has a long history. Research into the mechanisms responsible for this resistance is subsequently at a more advanced stage than for other classes of anthelmintics. The principal mechanism of resistance to benzimidazoles is likely to involve changes in the primary structure of β-tubulins, the building blocks of microtubules. Specifically, point mutations in the β-tubulin isotype 1 gene leading to amino acid substitutions in codons 167, 198, and 200 of the protein have been associated with resistance in nematodes. These single nucleotide polymorphisms offer a means of detecting the presence of resistance within populations. In this mini-review, we focus on the prevalence and importance of these polymorphisms in three groups of nematodes: trichostrongylids, cyathostomins, and hookworms. A brief overview of existing strategies for genotyping single nucleotide polymorphisms is also presented. The CARS initiative hopes to exploit these known polymorphisms to further our understanding of the phenomenon of BZ resistance.

Copyright

Corresponding author

*Corresponding author: Institute for Parasitology, University of Veterinary Medicine Foundation, Bünteweg 17, Hannover 30559, Germany. Tel: +49 511 953 8557. Fax: +49 511 953 8555. E-mail: Georg.von.Samson-Himmelstjerna@tiho-hannover.de

References

Hide All
Albonico, M., Bickle, Q., Ramsan, M., Montresor, A., Savioli, L. and Taylor, M. (2003). Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar. Bulletin of the World Health Organization 81, 343352.
Albonico, M., Wright, V. and Bickle, Q. (2004). Molecular analysis of the beta-tubulin gene of human hookworms as a basis for possible benzimidazole resistance on Pemba Island. Molecular and Biochemical Parasitology 134, 281284.
Álvarez-Sánchez, M. A., Pérez-García, J., Cruz-Rojo, M. A. and Rojo-Vázquez, F. A. (2005). Real time PCR for the diagnosis of benzimidazole resistance in trichostrongylids of sheep. Veterinary Parasitology 129, 291298.
Blackhall, W. J., Drogemuller, M., Schnieder, T. and Samson-Himmelstjerna, G. VON (2006). Expression of recombinant β-tubulin alleles from Cylicocyclus nassatus (Cyathostominae). Parasitology Research 99, 687693.
Caviston, J. P. and Holzbaur, E. L. (2006). Microtubule motors at the intersection of trafficking and transport. Trends in Cell Biology 16, 530537.
Cirak, V. Y., Gulegen, E. and Bauer, C. (2004). Benzimidazole resistance in cyathostomin populations on horse farms in western Anatolia, Turkey. Parasitology Research 93, 392395.
Clark, H. J., Kaplan, R. M., Matthews, J. B. and Hodgkinson, J. E. (2005). Isolation and characterisation of a beta tubulin isotype 2 gene from two species of cyathostomin. International Journal for Parasitology 35, 349358.
Crowe, M. L. (2005). SeqDoC: rapid SNP and mutation detection by direct comparison of DNA sequence chromatograms. BMC Bioinformatics 6, 133.
De Clercq, D., Sacko, M., Behnke, J., Gilbert, F., Dorny, P. and Vercruysse, J. (1997). Failure of mebendazole in treatment of human hookworm infections in the southern region of Mali. American Journal of Tropical Medicine and Hygiene 57, 2530.
Drogemuller, M., Failing, K., Schnieder, T. and Samson-Himmelstjerna, G. VON (2004). Effect of repeated benzimidazole treatments with increasing dosages on the phenotype of resistance and the beta-tubulin codon 200 genotype distribution in a benzimidazole-resistant cyathostomin population. Veterinary Parasitology 123, 201213.
Drogemuller, M., Schnieder, T. and Samson-Himmelstjerna, G. VON (2004). Beta-tubulin complementary DNA sequence variations observed between cyathostomins from benzimidazole-susceptible and -resistant populations. Journal of Parasitology 90, 868890.
Elard, L. and Humbert, J. F. (1999). Importance of the mutation of amino acid 200 of the isotype-1 β-tubulin gene in the benzimidazole-resistance of the small-ruminant parasite, Teladorsagia circumcincta. Parasitology Research 85, 452456.
Elard, L., Cabaret, J. and Humbert, J. F. (1999). PCR diagnosis of benzimidazole-susceptibility or -resistance in natural populations of the small ruminant parasite, Teladorsagia circumcincta. Veterinary Parasitology 80, 231237.
Elard, L., Sauve, C. and Humbert, J. F. (1998). Fitness of benzimidazole-resistant and -susceptible worms of Teladorsagia circumcincta, a nematode parasite of small ruminants. Parasitology 117, 571578.
Geary, T. G., Nulf, S. C., Favreau, M. A., Tang, L., Prichard, R. K., Hatzenbuhler, N. T., Shea, M. H., Alexander, S. J. and Klein, R. D. (1992). Three beta-tubulin cDNAs from the parasitic nematode Haemonchus contortus. Molecular and Biochemical Parasitology 50, 295306.
Geerts, S. and Gryseels, B. (2000). Drug resistance in human helminths: current situation and lessons from livestock. Clinical Microbiology Reviews 13, 207222.
Ghisi, M., Kaminsky, R. and Maser, P. (2007). Phenotyping and genotyping of Haemonchus contortus isolates reveals a new putative candidate mutation for benzimidazole resistance in nematodes. Veterinary Parasitology 144, 313320.
Grant, W. N. and Mascord, L. J. (1996). Beta-tubulin gene polymorphism and benzimidazole resistance in Trichostrongylus colubriformis. International Journal for Parasitology 26, 7177.
Hotez, P. J., Molyneux, D. H., Fenwick, A., Ottesen, E., Ehrlich Sachs, S. and Sachs, J. D. (2006). Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Medicine 3, e102.
Humbert, J. F., Cabaret, J., Elard, L., Leignel, V. and Silvestre, A. (2001). Molecular approaches to studying benzimidazole resistance in trichostrongylid nematode parasites of small ruminants. Veterinary Parasitology 101, 405414.
Jackson, R. A., Townsend, K. G., Pyke, C. and Lance, D. M. (1995). Isolation of oxfendazole resistant Cooperia oncophora in cattle. New Zealand Veterinary Journal 35, 187189.
Kaplan, R. M., Klei, T. R., Lyons, E. T., Lester, G., Courtney, C. H., French, D. D., Tolliver, S. C., Vidyashankar, A. N. and Zhao, Y. (2004). Prevalence of anthelmintic resistant cyathostomes on horse farms. Journal of the American Veterinary Medical Association 225, 903910.
Kaplan, R. M., Tolliver, S. C., Lyons, E. T., Chapman, M. R. and Klei, T. R. (2000). Characterization of β-tubulin genes from cyathostome populations with differing sensitivities to benzimidazole anthelmintics. In Proceedings of 45th Annual Meeting of the American Association of Veterinary Parasitologists, Salt Lake City, Utah, July 22–25, 2000, p. 82.
Kopp, S. R., Kotze, A. C., McCarthy, J. S. and Coleman, G. T. (2007). High-level pyrantel resistance in the hookworm Ancylostoma caninum. Veterinary Parasitology 143, 299304.
Kwa, M. S., Kooyman, F. N., Boersema, J. H. and Roos, M. H. (1993). Effect of selection for benzimidazole resistance in Haemonchus contortus on β-tubulin isotype 1 and isotype 2 genes. Biochemical and Biophysical Research Communications 191, 413419.
Kwa, M. S., Veenstra, J. G. and Roos, M. H. (1993). Molecular characterisation of β-tubulin genes present in benzimidazole-resistant populations of Haemonchus contortus. Molecular and Biochemical Parasitology 60, 133143.
Kwa, M. S., Veenstra, J. G. and Roos, M. H. (1994). Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in β-tubulin isotype 1. Molecular and Biochemical Parasitology 63, 299303.
Kwa, M. S., Veenstra, J. G., Van Dijk, M. and Roos, M. H. (1995). β-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. Journal of Molecular Biology 246, 500510.
Lacey, E. (1988). The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles. International Journal for Parasitology 18, 885936.
Li, J., Katiyar, S. K. and Edlind, E. T. (1996). Site-directed mutagenesis of Saccharomyces cerevisiae β-tubulin: interaction between residue 167 and benzimidazole compounds. FEBS Letters 385, 710.
Lubega, G. W. and Prichard, R. K. (1991). Interaction of benzimidazole anthelmintics with Haemonchus contortus tubulin: binding affinity and anthelmintic efficacy. Experimental Parasitology 73, 203213.
Margolis, R. L. and Wilson, L. (1998). Microtubule treadmilling: what goes around comes around. Bioessays 20, 830836.
Martin, P. J., Anderson, N. and Jarrett, R. G. (1989). Detecting benzimidazole resistance with faecal egg count reduction tests and in vitro assays. Australian Veterinary Journal 66, 236240.
Martin, R. J., Verma, S., Levandoski, M., Clark, C. L., Qian, H., Stewart, M. and Robertson, A. P. (2005). Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole. Parasitology 131, S71S84.
McKenna, P. B. (1996). Anthelmintic resistance in cattle nematodes in New Zealand, is it increasing? New Zealand Veterinary Journal 44, 76.
Meier, A. and Hertzberg, H. (2005). Equine strongyles II. Occurrence of anthelmintic resistance in Switzerland. Schweizer Archiv für Tierheilkunde 147, 389396.
Newton-Cheh, C. and Hirschhorn, J. N. (2005). Genetic association studies of complex traits: design and analysis issues. Mutation Research 573, 5469.
Njue, A. I. and Prichard, R. K. (2003). Cloning two full-length beta-tubulin isotype cDNAs from Cooperia oncophora, and screening for benzimidazole-associated mutations in two isolates. Parasitology 127, 579588.
Orbach, M. J., Porro, E. B. and Yanofsky, C. (1986). Cloning and characterization of the gene for β-tubulin from a benomyl-resistant mutant of Neurospora crassa and its use as a dominant selectable marker. Molecular and Cell Biology 6, 24522461.
Ottesen, E. A. (2006). Lymphatic filariasis: Treatment, control and elimination. Advances in Parasitology 61, 395441.
Pape, M., Posedi, J., Failing, K., Schnieder, T. and Samson-Himmelstjerna, G. VON (2003). Analysis of the beta-tubulin codon 200 genotype distribution in a benzimidazole-susceptible and -resistant cyathostome population. Parasitology 127, 5359.
Pape, M., Samson-Himmelstjerna, G. VON and Schnieder, T. (1999). Characterisation of the beta-tubulin gene of Cylicocyclus nassatus. International Journal for Parasitology 29, 19411947.
Pape, M., Schnieder, T. and Samson-Himmelstjerna, G. VON (2002). Investigation of diversity and isotypes of the beta-tubulin cDNA in several small strongyle (Cyathostominae) species. Journal of Parasitology 88, 673677.
Prichard, R. K. (2001). Genetic variability following selection of Haemonchus contortus with anthelmintics. Trends in Parasitology 17, 445453.
Prichard, R. K. (2002). Benzimidazole binding to Haemonchus contortus tubulin: a question of structure. Trends in Parasitology 18, 3.
Prichard, R. K., Oxberry, M., Bounhas, Y., Sharma, S., Lubega, G. and Geary, T. (2000). Polymerisation and benzimidazole binding assays with recombinant α- and β-tubulins from Haemonchus contortus. American Association of Veterinary Parasitologists. Forty-fifth Annual Meeting.
Reynoldson, J. A., Behnke, J. M., Pallant, L. J., Macnish, M. G., Gilbert, F., Giles, S., Spargo, R. J. and Thompson, R. C. (1997). Failure of pyrantel in treatment of human hookworm infections (Ancylostoma duodenale) in the Kimberley region of North West Australia. Acta Tropica 68, 301312.
Robinson, M., Trudgett, A., Fairweather, I. and McFerran, N. (2002). Benzimidazole binding to Haemonchus contortus tubulin: a question of structure. Trends in Parasitology 18, 153154.
Robinson, M. W., McFerran, N., Trudgett, A., Hoey, L. and Fairweather, I. (2004). A possible model of benzimidazole binding to beta-tubulin disclosed by invoking an interdomain movement. Journal of Molecular Graphics and Modelling 23, 275284.
Roos, M. H., Boersema, J. H., Borgsteede, F. H. M., Cornelissen, J., Taylor, M. and Ruitenberg, E. J. (1990). Molecular analysis of selection for benzimidazole resistance in the sheep parasite Haemonchus contortus. Molecular and Biochemical Parasitology 43, 7788.
Roos, M. H., Kwa, M. S. G. and Grant, W. N. (1995). New genetic and practical implications of selection for anthelmintic resistance in parasitic nematodes. Parasitology Today 11, 148150.
Samson-Himmelstjerna, G. VON and Blackhall, W. J. (2005). Will technology provide solutions for drug resistance in veterinary helminths? Veterinary Parasitology 132, 223239.
Samson-Himmelstjerna, G. VON, Buschbaum, S., Wirtherle, N., Pape, M. and Schnieder, T. (2003). TaqMan minor groove binder real-time PCR analysis of β-tubulin codon 200 polymorphism in small strongyles (Cyathostomin) indicates that the TAC allele is only moderately selected in benzimidazole-resistant populations. Parasitology 127, 489496.
Samson-Himmelstjerna, G. VON, Harder, A., Pape, M. and Schnieder, T. (2001). Novel small strongyle (Cyathostominae) beta-tubulin sequences. Parasitology Research 87, 122125.
Samson-Himmelstjerna, G. VON, Pape, M., von Witzendorff, C. and Schnieder, T. (2002 a). Allele-specific PCR for the beta-tubulin codon 200 TTC/TAC polymorphism using single adult and larval small strongyle (Cyathostominae) stages. Journal of Parasitology 88, 254257.
Samson-Himmelstjerna, G. VON, Witzendorff, C. VON, Sievers, G. and Schnieder, T. (2002 b). Comparative use of faecal egg count reduction test, egg hatch assay and beta-tubulin codon 200 genotyping in small strongyles (cyathostominae) before and after benzimidazole treatment. Veterinary Parasitology 108, 227235.
Schwab, A. E., Boakye, D. A., Kyelem, D. and Prichard, R. K. (2005). Detection of benzimidazole resistance-associated mutations in the filarial nematode Wuchereria bancrofti and evidence for selection by albendazole and ivermectin combination treatment. American Journal of Tropical Medicine and Hygiene 73, 234238.
Shayan, P., Eslami, A. and Hassan, B. (2007). Innovative restriction site created PCR-RFLP for detection of benzimidazole resistance in Teladorsagia circumcincta. Parasitology Research 100, 10631068.
Silvestre, A. and Cabaret, J. (2002). Mutation in position 167 of isotype 1 β-tubulin gene of Trichostrongylid nematodes: role in benzimidazole resistance? Molecular and Biochemical Parasitology 120, 297300.
Silvestre, A. and Humbert, J. F. (2000). A molecular tool for species identification and benzimidazole resistance diagnosis in larval communities of small ruminant parasites. Experimental Parasitology 95, 271276.
Silvestre, A. and Humbert, J. F. (2002). Diversity of benzimidazole-resistance alleles in populations of small ruminant parasites. International Journal for Parasitology 32, 921928.
Thomas, J. H., Neff, N. F. and Botstein, D. (1985). Isolation and characterization of mutations in the β-tubulin gene of Saccharomyces cerevisiae. Genetics 111, 715734.
Tiwari, J., Kumar, S., Kolte, A. P., Swarnkar, C. P., Singh, D. and Pathak, K. M. L. (2006). Detection of benzimidazole resistance in Haemonchus contortus using RFLP-PCR technique. Veterinary Parasitology 138, 301307.
Troell, K., Mattsson, J. G., Alderborn, A. and Hoglund, J. (2003). Pyrosequencing analysis identifies discrete populations of Haemonchus contortus from small ruminants. International Journal for Parasitology 33, 765771.
Varady, M., Konigova, A. and Corba, J. (2000). Benzimidazole resistance in equine cyathostomes in Slovakia. Veterinary parasitology 94, 6774.
Walsh, T. K., Donnan, A. A., Jackson, F., Skuce, P. J. and Wolstenholme, A. J. (2007). Detection and measurement of benzimidazole resistance alleles in Haemonchus contortus using real-time PCR with locked nucleic acid Taqman probes. Veterinary Parasitology 144, 304312.
Wilson, L., Panda, D. and Jordan, M. A. (1999). Modulation of microtubule dynamics by drugs: a paradigm for the actions of cellular regulators. Cell Structure and Function 24, 329335.
Winterrowd, C. A., Pomroy, W. E., Sangster, N. C., Johnson, S. S. and Geary, T. G. (2003). Benzimidazole-resistant β-tubulin alleles in a population of parasitic nematodes (Cooperia oncophora). Veterinary Parasitology 117, 161172.
Wirtherle, N., Schnieder, T. and Samson-Himmelstjerna, G. VON (2004). Prevalence of benzimidazole resistance on horse farms in Germany. Veterinary Record 154, 3941.
Wolstenholme, A. J., Fairweather, I., Prichard, R. K., Samson-Himmelstjerna, G. VON and Sangster, N. C. (2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 469476.

Keywords

Single nucleotide polymorphism (SNP) markers for benzimidazole resistance in veterinary nematodes

  • G. VON SAMSON-HIMMELSTJERNA (a1), W. J. BLACKHALL (a1), J. S. McCARTHY (a2) and P. J. SKUCE (a3)

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed