Ivermectin imposes selection pressure on P-glycoprotein from Onchocerca volvulus: linkage disequilibrium and genotype diversity | Parasitology | Cambridge Core (original) (raw)

Abstract

Widespread use of ivermectin (IVM) as part of the Onchocerciasis Control Program (OCP) in West Africa could influence the evolution of the human filarial parasite Onchocerca volvulus. Use of IVM, in some areas for 15 years, may have restricted genetic diversity of O. volvulus, resembling effects attributed to a population bottleneck. Large population-based chemotherapy programmes, such as the OCP, may impose strong selection pressure on parasites and an examination of possible genetic selection by IVM in O. volvulus is warranted. IVM is a substrate for P-glycoprotein; a homologue from O. volvulus (OvPGP) has been linked with IVM sensitivity. Linkage disequilibrium (LD) patterns of 28 genetic markers spanning the OvPGP locus were examined in 4 O. volvulus populations from the Volta Region of Ghana, West Africa. Reduced gene diversity, increased heterozygosity and an increase in the number of markers not in Hardy-Weinberg equilibrium were associated with increasing IVM treatment. The number of regions in LD decreased with treatment and with time. However, between 1999 and 2002, seven regions of OvPGP were always in complete LD, while surrounding areas showed a reduction in genetic variation. The use of IVM for onchocerciasis control has imposed strong selection on O. volvulus populations, reducing genetic variation and disrupting LD.

References

Ali, M. M.,Mukhtar, M. M.,Baraka, O. Z.,Homeida, M. M.,Kheir, M. M. andMackenzie, C. D. (2002).Immunocompetence may be important in the effectiveness of Mectizan (ivermectin) in the treatment of human onchocerciasis.Acta Tropica 84,49–53.CrossRefGoogle Scholar

Ardelli, B. F.,Guerriero, S. B. andPrichard, R. K. (2005).Genomic organization and effects of ivermectin selection on Onchocerca volvulus P-glycoprotein.Molecular and Biochemical Parasitology 143,58–66.CrossRefGoogle Scholar

Ardelli, B. F. andPrichard, R. K. (2004).Identification of variant ABC transporter genes among Onchocerca volvulus collected from ivermectin treated and untreated patients in Ghana, West Africa.Annals of Tropical Medicine and Parasitology 98,371–384.CrossRefGoogle Scholar

Awadzi, K.,Attah, S. K.,Addy, E. T.,Opoku, N. O. andQuartey, B. T. (1999).The effects of high-dose ivermectin regimens on Onchocerca volvulus in onchocerciasis patients.Transactions of the Royal Society of Tropical Medicine and Hygiene 93,189–194.CrossRefGoogle Scholar

Awadzi, K.,Attah, S. K.,Addy, E. T.,Opoku, N. O.,Quartey, B. T.,Lazdins-Helds, J. K.,Ahmed, K.,Boatin, B. A.,Boakye, D. A. andEdwards, G. (2004 b).Thirty-month follow-up of sub-optimal responders to multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana.Annals of Tropical Medicine and Parasitology 98,359–370.Google Scholar

Awadzi, K.,Boakye, D. A.,Edwards, G.,Opoku, N. O.,Attah, S. K.,Osei-Atweneboana, M. Y.,Lazdins-Helds, J. K.,Ardrey, A. E.,Addy, E. T.,Quartey, B. T.,Ahmed, K.,Boatin, B. A. andSoumbey-Alley, E. W. (2004 a).An investigation of persistent microfilaridermia despite multiple treatments with ivermectin in two onchocerciasis endemic foci in Ghana.Annals of Tropical Medicine and Parasitology 98,231–249.Google Scholar

Basáñez, M. G.,Townson, H.,Williams, J. R.,Frontado, H.,Villamizar, N. J. andAnderson, R. M. (1996).Density-dependent processes in the transmission of human onchocerciasis: relationship between microfilarial intake and mortality of the simuliid vector.Parasitology 113,331–355.CrossRefGoogle Scholar

Blackhall, W.,Liu, H. Y.,Xu, M.,Prichard, R. K. andBeech, R. N. (1998).Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus.Molecular and Biochemical Parasitology 95,193–201.CrossRefGoogle Scholar

Carmichael, I.,Visser, R.,Schneider, D. andSoll, M. (1987).Haemonchus contortus resistance to ivermectin.Journal of the South African Veterinary Association 58,93.Google Scholar

Dadzie, Y.,Neira, M. andHopkins, D. (2003).Final report of the Conference on the eradicability of Onchocerciasis.Filaria Journal 2,2.CrossRefGoogle Scholar

Didier, A. andLoor, F. (1996).The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor.Anticancer Drugs 7,745–751.CrossRefGoogle Scholar

Dobson, R. J.,Le Jambre, L. andGill, J. H. (1996).Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs.International Journal for Parasitology 26,993–1000.CrossRefGoogle Scholar

Duke, B. O.,Zea-Flores, G.,Castro, J.,Cupp, E. W. andMunoz, B. (1992).Effects of three-month doses of ivermectin on adult Onchocerca volvulus.American Journal of Tropical Medicine and Hygiene 46,189–194.CrossRefGoogle Scholar

Duke, B. O.,Zea-Flores, G.,Castro, J.,Cupp, E. W. andMunoz, B. (1990).Effects of multiple monthly doses of ivermectin on adult Onchocerca volvulus.American Journal of Tropical Medicine and Hygiene 43,657–664.CrossRefGoogle Scholar

Eng, J. K. L. andPrichard, R. K. (2005).A comparison of genetic polymorphism in populations of Onchocerca volvulus from untreated- and ivermectin-treated patients.Molecular and Biochemical Parasitology 142,193–202.CrossRefGoogle Scholar

Gardon, J.,Boussinesq, M.,Kamgno, J.,Gardon-Wendel, N.,Demanga-Ngangue andDuke, B. O. (2002).Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial.Lancet 360,203–210.CrossRefGoogle Scholar

Garms, R.,Walsh, J. F. andDavies, J. B. (1979).Studies on the reinvasion of the Oncocerciasis Control Program in the Volta River Basin by Simulium damnosum s.i. with emphasis on the south-western areas.Tropenmedizin and Parasitologie 30,345–362.Google Scholar

Green, B. M.,Brown, K. R. andTaylor, H. R. (1989).Use of ivermectin in humans. In_Ivermectin and Abamectin_ ( ed. Campbell, W. C.), pp.311–323.Springer-Verlag,New York.CrossRef

Hartl, D. L. andClark, A. G. (1999).Principles of Population Genetics.Sinauer,Sutherland, Massachusetts.

Herlich, H.,Rew, R. S. andColglazier, M. L. (1981).Inheritance of cambendazole resistance in Haemonchus contortus.American Journal of Veterinary Research 42,1342–1344.Google Scholar

Huang, Y.-J. andPrichard, R. K. (1999).Identification and stage-specific expression of two putative P-glycoprotein coding genes in Onchocerca volvulus.Molecular and Biochemical Parasitology 102,273–281.CrossRefGoogle Scholar

Juliano, R. L. andLing, V. (1976).A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.Biochimica et Biophysica Acta 455,152–162.CrossRefGoogle Scholar

Kerboeuf, D.,Blackhall, W.,Kaminsky, R. andvon Samson-Himmelstjerna, G. (2003).P-glycoprotein in helminths: function and perspectives for anthelmintic treatment and reversal of resistance.International Journal of Antimicrobial Agents 22,332–346.CrossRefGoogle Scholar

Kis-Papo, T.,Kirzhner, V.,Wasser, S. P. andNevo, E. (2003).Evolution of genomic diversity and sex at extreme environments: fungal life under hypersaline Dead Sea stress.Proceedings of the National Academy of Sciences, USA 100,14970–14975.CrossRefGoogle Scholar

Le Jambre, L. F.,Lenane, I. J. andWardrop, A. J. (1999).A hybridization technique to identify anthelmintic resistance genes in Haemonchus.International Journal for Parasitology 29,1979–1985.Google Scholar

Le Jambre, L. F.,Royal, W. M. andMartin, P. J. (1979).The inheritance of thiabendazole resistance in Haemonchus contortus.Parasitology 78,107–119.CrossRefGoogle Scholar

Lincke, C. R.,Broeks, A.,The, I.,Plasterk, R. H. andBorst, P. (1993).The expression of two P-glycoprotein (pgp) genes in transgenic Caenorhabditis elegans is confined to intestinal cells.EMBO Journal 12,1615–1620.Google Scholar

Nei, M. (1987).Molecular Evolutionary Genomics.Columbia University Press,New York.

Nei, M. andLi, W. H. (1979).Mathematical model for studying genetic variation in terms of restriction endonucleases.Proceedings of the National Academy of Sciences, USA 76,5269–5273.CrossRefGoogle Scholar

Niu, T.,Qin, Z. S.,Xu, X. andLiu, J. S. (2002).Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms.American Journal of Human Genetics 70,157–169.CrossRefGoogle Scholar

Plaisier, A. P.,Alley, E. S.,Boatin, B. A.,Van Oortmarssen, G. J.,Remme, H.,De Vlas, S. J.,Bonneux, L. andHabbema, J. D. (1995).Required duration of combined annual ivermectin treatment and vector control in the Onchocerciasis Control Programme in West Africa.Journal of Infectious Disease 172,204–210.CrossRefGoogle Scholar

Pouliot, J. F.,L'Heureux, F.,Liu, Z.,Prichard, R. K. andGeorges, E. (1997).Reversal of P-glycoprotein-associated multidrug resistance by ivermectin.Biochemical Pharmacology 53,17–25.CrossRefGoogle Scholar

Sangster, N. C.,Bannan, S. C.,Weiss, A. S.,Nulf, S. C.,Klein, R. D. andGeary, T. G. (1999).Haemonchus contortus: sequence heterogeneity of internucleotide binding domains from P-glycoproteins.Experimental Parasitology 91,250–257.CrossRefGoogle Scholar

Soumbey-Alley, E.,Basanez, M. G.,Bissan, Y.,Boatin, B. A.,Remme, J. H.,Nagelkerke, N. J.,de Vlas, S. J.,Borsboom, G. J. andHabbema, J. D. (2004).Uptake of Onchocerca volvulus (Nematoda: Onchocercidae) by Simulium (Diptera: Simuliidae) is not strongly dependent on the density of skin microfilariae in the human host.Journal of Medical Entomology 41,83–94.CrossRefGoogle Scholar

Wolstenholme, A. J.,Fairweather, I.,Prichard, R.,von Samson-Himmelstjerna, G. andSangster, N. C. (2004).Drug resistance in veterinary helminths.Trends in Parasitology 20,469–476.CrossRefGoogle Scholar

Xu, M.,Molento, M.,Blackhall, W.,Ribeiro, P.,Beech, R. andPrichard, R. (1998).Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog.Molecular and Biochemical Parasitology 91,327–335.CrossRefGoogle Scholar