Abstract
While diseases caused by nematodes remains a considerable drawback for the livestock, agriculture and public health, anthelmintics drug resistance has been observed over the past years and is a major concern for parasite control. Ivermectin, initially considered as a highly potent drug, currently presents a reduced anti-helminthic efficacy, which is influenced by expression of several ATP-binding cassette transporters (ABC), among them the P-glycoproteins (Pgps). Here we present some evidences of Pgps dominance during Ivermectin resistance/susceptibility using Pgps double silencing in C. elegans and the phylogenetic relationship of Pgps among nematodes, which strengthen the use of this model for study of drug resistance in nematodes. Firstly, we evaluated the quantitative gene expression of 12 out the 15 known Pgps from resistant and WT strains of C. elegans, we demonstrated the upregulation of Pgps 12 and 13 and downregulation of all remaining Pgps in ivermectin resistant strain. By using an RNAi loss-of-function approach we observed that Pgp 12 gene silencing reverts the resistance phenotype to ivermectin, while Pgp 4 gene silencing does not alter the resistance phenotype but induces a resistance in wild type strain. Interestingly, the dual silencing of Pgp 12 and Pgp 4 expression demonstrates the dominance of phenotype promoted by Pgp 12 silencing. Finally, in silico analysis reveals a close relationship between Pgps from C. elegans and several nematodes parasites. Taken together, our results indicate that Pgp 12 is crucial for the resistance to ivermectin and thus a good candidate for further studies aiming to develop specific inhibitors to this transporter, allowing the continuous use of ivermectin to control the burden on animal and human health inflicted by nematode parasites globally.
Highlights
Diseases caused by nematodes remains a considerable drawback for the livestock, agriculture and public health, contributing to increasing production costs, decreased food supply and deficits in host health [1,2]
The ubiquitous use of this drug has led to the selection of resistance in several target species including Cooperia oncophora [7], Haemonchus contortus [8], Ostertagia spp. [7], Trichostrongylus spp. [8], Onchocerca volvulus [4, 9,10] and Dirofilaria immitis [11,12]
Previous studies have shown that macrocyclic lactone (ML) anthelmintics can be transported by several ATPbinding cassette transporters (ABC), whose expression levels might be regulated in ML resistant nematodes [13,14,15]
Summary
Diseases caused by nematodes remains a considerable drawback for the livestock, agriculture and public health, contributing to increasing production costs, decreased food supply and deficits in host health [1,2]. Previous studies have shown that ML anthelmintics can be transported by several ATPbinding cassette transporters (ABC), whose expression levels might be regulated in ML resistant nematodes [13,14,15]. Among these ABC transporters, the P-glycoproteins (Pgps) are known to perform cell efflux of several foreign substances [13,14,15,16] and their overexpression are related to multidrug resistance in mammalian cells and human tumor cells [17,18]. The relationship between Pgps and ivermectin resistance in nematodes has been shown [13, 14, 16, 19,20], here we present some evidences of Pgps dominance using Pgps double silencing in C. elegans and the phylogenetic relationship of Pgps among nematodes, which strengthen the use of this model for study of drug resistance in nematodes
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