GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance

Atif, Mohammed; Smith, Jennifer J.; Estrada-Mondragón, Argel; Xiao, Xue; Salim, Angela A.; Capon, Robert J.; Lynch, Joseph W.; Keramidas, Angelo

doi:10.1371/journal.ppat.1007570

Cited by 24 publications

(33 citation statements)

References 52 publications

(82 reference statements)

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“…One of our candidate genes encodes glutamate-gated chloride channel (HCON_00148840, glc-3), and it has been analyzed as IVM-resistance-associated candidate previously [68][69][70]. The glutamate-gated chloride channel is the direct target site of IVM, where IVM binds irreversibly [71,72].…”

Section: Discussionmentioning

confidence: 99%

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Khan

Nisar

Yuan

et al. 2020

Genes

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The most important and broad-spectrum drug used to control the parasitic worms to date is ivermectin (IVM). Resistance against IVM has emerged in parasites, and preserving its efficacy is now becoming a serious issue. The parasitic nematode Haemonchus contortus (Rudolphi, 1803) is economically an important parasite of small ruminants across the globe, which has a successful track record in IVM resistance. There are growing evidences regarding the multigenic nature of IVM resistance, and although some genes have been proposed as candidates of IVM resistance using lower magnification of genome, the genetic basis of IVM resistance still remains poorly resolved. Using the full magnification of genome, we herein applied a population genomics approach to characterize genome-wide signatures of selection among pooled worms from two susceptible and six ivermectin-resistant isolates of H. contortus, and revealed candidate genes under selection in relation to IVM resistance. These candidates also included a previously known IVM-resistance-associated candidate gene HCON_00148840, glc-3. Finally, an RNA-interference-based functional validation assay revealed the HCON_00143950 as IVM-tolerance-associated gene in H. contortus. The possible role of this gene in IVM resistance could be detoxification of xenobiotic in phase I of xenobiotic metabolism. The results of this study further enhance our understanding on the IVM resistance and continue to provide further evidence in favor of multigenic nature of IVM resistance.

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Section: Discussionmentioning

confidence: 99%

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Khan

Nisar

Yuan

et al. 2020

Genes

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“…Two of the drugs commonly used to treat parasitic nematode infections include ivermectin, which targets an invertebrate-specific chloride channel, and albendazole, which targets β-tubulin (Atif et al, 2019;Prichard et al, 2012). However, these drugs do not prevent reinfection (Prichard et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in functional genomics for parasitic nematodes of mammals

Castelletto

Gang

Hallem

2020

Journal of Experimental Biology

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Human-parasitic nematodes infect over a quarter of the world's population and are a major cause of morbidity in low-resource settings. Currently available treatments have not been sufficient to eliminate infections in endemic areas, and drug resistance is an increasing concern, making new treatment options a priority. The development of new treatments requires an improved understanding of the basic biology of these nematodes. Specifically, a better understanding of parasitic nematode development, reproduction and behavior may yield novel drug targets or new opportunities for intervention such as repellents or traps. Until recently, our ability to study parasitic nematode biology was limited because few tools were available for their genetic manipulation. This is now changing as a result of recent advances in the large-scale sequencing of nematode genomes and the development of new techniques for their genetic manipulation. Notably, skin-penetrating gastrointestinal nematodes in the genus Strongyloides are now amenable to transgenesis, RNAi and CRISPR/Cas9-mediated targeted mutagenesis, positioning the Strongyloides species as model parasitic nematode systems. A number of other mammalian-parasitic nematodes, including the giant roundworm Ascaris suum and the tissue-dwelling filarial nematode Brugia malayi, are also now amenable to transgenesis and/or RNAi in some contexts. Using these tools, recent studies of Strongyloides species have already provided insight into the molecular pathways that control the developmental decision to form infective larvae and that drive the host-seeking behaviors of infective larvae. Ultimately, a mechanistic understanding of these processes could lead to the development of new avenues for nematode control.

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Section: Discussionmentioning

confidence: 99%

“…Ivermectin interacts with the glutamate-gated chloride channel receptors (GluClRs) activity that mediate neuronal and muscular inhibition [16]. However, GluCIRs are expressed exclusively in invertebrates [16]. In the mammalian central nervous system (CNS), ivermectin interacts with at least three targets: a GABA-dependent chloride channel, a glycine-dependent chloride channel and a voltage-dependent channel [17,18].…”

Section: Discussionmentioning

confidence: 99%

Single versus Multiple Dose Ivermectin Regimen in Onchocerciasis-Infected Persons with Epilepsy Treated with Phenobarbital: A Randomized Clinical Trial in the Democratic Republic of Congo

Mandro¹,

Fodjo

Dusabimana

et al. 2020

Pathogens

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Background: There is anecdotal evidence that ivermectin may decrease seizure frequency in Onchocerca volvulus-infected persons with epilepsy (PWE). Methods: In October 2017, a 12-month clinical trial was initiated in rural Democratic Republic of Congo. PWE with onchocerciasis-associated epilepsy experiencing ≥2 seizures/month were randomly allocated to receive, over a one-year period, ivermectin once or thrice (group 1), while other onchocerciasis-infected PWE (OIPWE) were randomized to ivermectin twice or thrice (group 2). All participants also received anti-epileptic drugs. Data was analyzed using multiple logistic regression. Results: We enrolled 197 participants. In an intent-to-treat analysis (data from group 1 and 2 combined), seizure freedom was more likely among OIPWE treated with ivermectin thrice (OR: 5.087, 95% CI: 1.378–19.749; p = 0.018) and twice (OR: 2.471, 95% CI: 0.944–6.769; p = 0.075) than in those treated once. Similarly, >50% seizure reduction was more likely among those treated with ivermectin twice (OR: 4.469, 95% CI: 1.250–16.620) and thrice (OR: 2.693, 95% CI: 1.077–6.998). Absence of microfilariae during the last 4 months increased the odds of seizure freedom (p = 0.027). Conclusions: Increasing the number of ivermectin treatments was found to suppress both microfilarial density and seizure frequency in OIPWE, suggesting that O. volvulus infection plays an etiological role in causing seizures.

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GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance

Cited by 24 publications

References 52 publications

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

A Whole Genome Re-Sequencing Based GWA Analysis Reveals Candidate Genes Associated with Ivermectin Resistance in Haemonchus contortus

Recent advances in functional genomics for parasitic nematodes of mammals

Single versus Multiple Dose Ivermectin Regimen in Onchocerciasis-Infected Persons with Epilepsy Treated with Phenobarbital: A Randomized Clinical Trial in the Democratic Republic of Congo

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