Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs

Pulaski, Cassan N.; Malone, John B.; Bourguinat, Catherine; Prichard, Roger K.; Geary, Timothy G.; Ward, Danielle; Klei, Thomas R.; Guidry, Tal; Smith, George Davey; Delcambre, Brooke; Bova, Jonathan; Pepping, Jenny; Carmichael, James; Schenker, R.; Pariaut, Romain

doi:10.1186/preaccept-5912484341258228

Cited by 39 publications

(53 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the importance of the macrocyclic lactones in the control of heartworm and human filariases, together with the emergence of resistance to the drugs in D. immitis (Bourguinat et al 2015; Wolstenholme et al 2015; Pulaski 2014; Geary et al 2011) and reports of reduced drug efficacy in some Onchocerca volvulus patients (Osei-Atweneboana et al 2011) it is essential that we understand how they work against these parasites. Bioinformatic analysis indicates that filarial species have lost many genes encoding ligand-gated ion channels, including many of the GluCl-encoding genes, when compared to other nematodes (Williamson et al 2007; Beech and Neveu 2015).…”

Section: Anthelmintic Effects Of Macrocyclic Lactones In Filarial Infmentioning

confidence: 99%

How do the macrocyclic lactones kill filarial nematode larvae?

Wolstenholme¹,

MacLean²,

Coates

et al. 2016

Invert Neurosci

View full text Add to dashboard Cite

The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.

show abstract

Section: Anthelmintic Effects Of Macrocyclic Lactones In Filarial Infmentioning

confidence: 99%

How do the macrocyclic lactones kill filarial nematode larvae?

Wolstenholme¹,

MacLean²,

Coates

et al. 2016

Invert Neurosci

View full text Add to dashboard Cite

show abstract

“…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%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In dogs experimentally infected with two different heartworm isolates taken from suspected lack-of-efficacy cases from the Delta region, the parasites survived repeated treatment with a macrocyclic lactone. The dogs received double the recommended dose, monthly for six months, under the watchful eye of veterinarians 4 . "There's no question that these are resistant parasites, " says Wolstenholme, who has had similar findings in his own research into resistant strains.…”

Section: Rumour Versus Realitymentioning

confidence: 99%

Dogs: The riddle of resistance

Eisenstein¹

2017

Nature

View full text Add to dashboard Cite

Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs

Cited by 39 publications

References 24 publications

How do the macrocyclic lactones kill filarial nematode larvae?

How do the macrocyclic lactones kill filarial nematode larvae?

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

Dogs: The riddle of resistance

Contact Info

Product

Resources

About