Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance

Bourguinat, Catherine; Lee, Alice C.Y.; Lizundia, Regina; Blagburn, Byron L.; Liotta, Janice L.; Kraus, Marc S.; Keller, Kathy; Epe, Christian; Létourneau, Louis; Kleinman, Claudia L.; Paterson, Tara; Gómez, Elena Carretón; Montoya-Alonso, José Alberto; Smith, Hubert; Bhan, Aron; Peregrine, Andrew S.; Carmichael, James; Drake, Jason; Schenker, R.; Kaminsky, Ronald; Bowman, Dwight D.; Geary, Timothy G.; Prichard, Roger K.

doi:10.1016/j.vetpar.2015.04.002

Cited by 135 publications

(164 citation statements)

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“…Whole genome sequencing data were generated, from 122 ML susceptible adult worms, isolated from 17 dogs from 4 countries, for SNP analysis. In the case of LOE samples, ∼32,000 mf, isolated from 4 ML-LOE dogs from different US states were used (Bourguinat et al., 2015). It is possible that some additional SNPs were not detected in this analysis due to lack of coverage of some sequences in the genome or to the population size and diversity that was analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…The nDi.2.2 genome of D. immitis is in draft stage (Godel, 2012) and the gene annotation is not complete (Bourguinat et al., 2015). A complete inventory of ion channel genes of D. immitis is not available.…”

Section: Methodsmentioning

confidence: 99%

“…Pooled worm samples and the method followed for synchronized file generation for genetic variability analysis were as previously described (Bourguinat et al., 2015) except that the reference genome used was different in this study. Briefly, our study samples included a total of 122 worms from 17 ML susceptible dogs from the USA (Missouri isolate), Gran Canary (Spain), Grenada (West Indies) and Italy (Po Basin, Northern Italy).…”

Section: Methodsmentioning

confidence: 99%

“…We also thank Adebola Razaki for helping us with some Java scripts. We thank Dr Christian Epe, Dr Tara Paterson and Dr Byron Blagburn for providing D. immitis samples that were used in the original genome sequencing (Bourguinat et al., 2015) which generated sequence information that facilitated the search for polymorphism in ion channel genes in the present study.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…However, there have been reports of loss of efficacy (LOE) of these MLs against heartworm in the USA, especially in those areas where heartworm challenge is high (Hampshire, 2005). Recent studies have confirmed, using in vivo efficacy studies and genetic analysis, actual ML resistance in D. immitis (Bourguinat et al., 2011a, Bourguinat et al., 2015, Pulaski et al., 2014). There also exists some evidence of ML resistance in the human parasite, Onchocerca volvulus (Osei-Atweneboana et al., 2007, Osei-Atweneboana et al., 2011, Nana-Djeunga et al., 2012, Nana-Djeunga et al., 2014, Pion et al., 2013), a filarial nematode which is closely related to D. immitis .…”

Section: Introductionmentioning

confidence: 99%

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Polymorphism in ion channel genes of Dirofilaria immitis : Relevant knowledge for future anthelmintic drug design

Mani

Bourguinat

Keller

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite. Any new drug that targets these ion channels is likely to have a motility phenotype and should act to clear the worms from the host. Many of the successful anthelmintics in the past have targeted these ion channels and receptors. Knowledge about genetic variability of the ion channel and receptor genes should be useful information for drug design as receptor polymorphism may affect responses to a drug. Such information may also be useful for anticipation of possible resistance development. A total of 224 ion channel genes/subunits have been identified in the genome of D. immitis. Whole genome sequencing data of parasites from eight different geographical locations, four from ML-susceptible populations and the other four from ML-loss of efficacy (LOE) populations, were used for polymorphism analysis. We identified 1762 single nucleotide polymorphic (SNP) sites (1508 intronic and 126 exonic) in these 224 ion channel genes/subunits with an overall polymorphic rate of 0.18%. Of the SNPs found in the exon regions, 129 of them caused a non-synonymous type of polymorphism. Fourteen of the exonic SNPs caused a change in predicted secondary structure. A few of the SNPs identified may have an effect on gene expression, function of the protein and resistance selection processes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Acknowledgementsmentioning

confidence: 99%