P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus

Bourguinat, Catherine; Ardelli, Bernadette F.; Pion, S. D. S.; Kamgno, Joseph; Gardon, Jacques; Duke, B. O. L.; Boussinesq, Michel; Prichard, Roger K.

doi:10.1016/j.molbiopara.2007.11.017

Cited by 77 publications

(63 citation statements)

References 36 publications

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“…Estimation of the host's skin repopulation rate provides a method of quantifying an individual host's response to treatment which can be correlated with the genotypic information of parasites obtained from that host (microfilariae and adult worms). A number of possible molecular markers (including beta-tubulin and Pglycoprotein among others) have been identified which could provide useful tools in identifying anthelmintic resistance before it becomes widely spread (32,33). Linking phenotypic responses with molecular genetics markers will be required to prove that suboptimal responses are in fact due to drug-resistant parasites and not to host-related factors (3).…”

Section: Discussionmentioning

confidence: 99%

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

Churcher

Pion

Osei-Atweneboana

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Identification of drug resistance before it becomes a public health concern requires a clear distinction between what constitutes a normal and a suboptimal treatment response. A novel method of analyzing drug efficacy studies in human helminthiases is proposed and used to investigate recent claims of atypical responses to ivermectin in the treatment of River Blindness. The variability in the rate at which Onchocerca volvulus microfilariae repopulate host's skin following ivermectin treatment is quantified using an individual-based onchocerciasis mathematical model. The model estimates a single skin repopulation rate for every host sampled, allowing reports of suboptimal responses to be statistically compared with responses from populations with no prior exposure to ivermectin. Statistically faster rates of skin repopulation were observed in 3 Ghanaian villages (treated 12-17 times), despite the wide variability in repopulation rates observed in ivermectin-naïve populations. Another village previously thought to have high rates of skin repopulation was shown to be indistinguishable from the normal treatment response. The model is used to generate testable hypotheses to identify whether atypical rates of skin repopulation by microfilariae could result from low treatment coverage alone or provide evidence of decreased ivermectin efficacy. Further work linking phenotypic poor responses to treatment with parasite molecular genetics markers will be required to confirm drug resistance. Limitations of the skin-snipping method for estimating parasite load indicates that changes in the distribution of microfilarial repopulation rates, rather than their absolute values, maybe a more sensitive indicator of emerging ivermectin resistance. drug resistance ͉ helminth parasites ͉ Onchocerca volvulus ͉ overdispersion

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Section: Discussionmentioning

confidence: 99%

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

Churcher

Pion

Osei-Atweneboana

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, while adults showed changes in transcriptional profiles of some ABC systems following IVM exposure and sensitivity to IVM increased following coadministration of some PGP-interfering agents, these results cannot identify which of the ABC systems, or related pathways, may be specifically targeted by IVM. While a number of studies have reported an association between ABC genes (and specific SNPs) and IVM in O. volvulus and other nematodes Ardelli and Prichard 2004;Ardelli et al 2005Ardelli et al , 2006aEng and Prichard 2005;Ardelli and Prichard 2007;Bourguinat et al 2008), none have provided evidence as to the functional significance, if any, of these SNPs. While the complex life cycles of filarioids and the inability to maintain many of these infections in animal models or in vivo has contributed to the lack of progress in functional studies, a concerted effort should be made to determine which ABC systems are substrates for IVM and the functional significance of the SNPs identified.…”

Section: Discussionmentioning

confidence: 99%

“…Resistance to IVM has been reported in O. volvulus (Awadzi et al 2004a, b;Osei-Atweneboana et al 2007) and, based on these studies, it could develop in Brugia and Wuchereria. Studies of O. volvulus removed from patients that had received multiple IVM treatments have indicated that members of the ABC superfamily might be a factor contributing to reduced drug efficacy Prichard 2004, 2007;Ardelli et al 2005Ardelli et al , 2006aEng and Prichard 2005;Bourguinat et al 2008). A knowledge of inhibitors of ABC protein drug efflux would help in the development of short-term strategies to improve bioavailability of IVM in the host and the parasite, if ABC systems are contributing to reduced IVM efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, while glutamate-gated chloride channels are the sole target of IVM and account for its mechanism of action, it is possible that resistance is caused by additional targets. For example, in nematodes showing resistance to or tolerance of IVM, PGP, or MRP have been cited as a contributing factor (Ardelli and Prichard 2004Ardelli et al 2005Ardelli et al , 2006aBartley et al 2009;Blackhall et al 1998;Bourguinat et al 2008;Eng and Prichard 2005;Huang and Prichard 1999;James and Davey 2009;Kerboeuf et al 2003;Le Jambre et al 1999;Molento and Prichard 1999;Sangster et al 1999;Smith and Prichard 2002;Xu et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

et al. 2011

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ATP binding cassette (ABC) systems are a diverse group of proteins that have been identified in every organism, from bacteria to humans. Analysis of nematode genomes indicates that the number and arrangement of ABC systems are similar to other organisms, with the majority being ABC transporters. There are few functional studies of ABC transporters in parasitic nematodes; most reports have been on their identification or use as genetic markers to monitor drug resistance. In eukaryotes, some ABC transporters function in tissue defense by actively removing drugs, thus preventing their accumulation. The overexpression of ABC transporters that function as efflux pumps, such as P-glycoprotein (PGP) and the multidrug resistance associated protein (MRP) are known to confer resistance. Drug sensitivity can be restored by administration of PGP interfering or MDR reversal agents. The objective of this study was to determine if ABC systems in filarioid nematodes function similarly to those of other organisms. The relative expression of 33 ABC systems identified in Brugia malayi was quantified following exogenous exposure to the commonly used drug ivermectin (IVM). Following exposure of adults and microfilariae to IVM, there was a significant increase in the transcriptional profiles of a number of ABC systems, mostly within the PGP and MRP subgroups. Coadministration of PGP-interfering and MDR-reversal agents with IVM potentiated sensitivity to the drug in adults and microfilariae. The results suggest that B. malayi ABC transporters function similarly to those in other organisms and are a factor in determining drug sensitivity.

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“…In parasitic nematodes, eight P-gp, five MRPs and eight HAF transporter genes were reported in Brugia malayi (Ardelli et al, 2010), two P-gp genes in cyathostomins (Drogemuller et al, 2004), 11 partial sequences of P-gp genes in Te. circumcincta (Dicker et al, 2011) and four P-gp and three HAF encoding genes have been reported in Onchocerca volvulus (Huang and Prichard, 1999;Bourguinat et al, 2008). Whereas, in H. contortus, 11 P-gp genes, one HAF gene and two MRP genes have been reported (Williamson and Wolstenholme, 2012;Laing et al, 2013).…”

Section: Abc Transporters In Nematodesmentioning

confidence: 99%

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

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P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus

Cited by 77 publications

References 36 publications

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

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