The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis.

Nicolas Lamassiaude,Isabelle Dimier-Poisson,Catherine Dupuy,Claude L Charvet,Berthine Toubate,Françoise Debierre-Grockiego,Cédric Neveu,Pierre Charnet,Timothy G Geary

doi:10.1371/journal.ppat.1008863

Abstract

Control of infestation by cosmopolitan lice (Pediculus humanus) is increasingly difficult due to the transmission of parasites resistant to pediculicides. However, since the targets for pediculicides have no been identified in human lice so far, their mechanisms of action remain largely unknown. The macrocyclic lactone ivermectin is active against a broad range of insects including human lice. Isoxazolines are a new chemical class exhibiting a strong insecticidal potential. They preferentially act on the γ-aminobutyric acid (GABA) receptor made of the resistant to dieldrin (RDL) subunit and, to a lesser extent on glutamate-gated chloride channels (GluCls) in some species. Here, we addressed the pediculicidal potential of isoxazolines and deciphered the molecular targets of ivermectin and the ectoparasiticide lotilaner in the human body louse species Pediculus humanus humanus. Using toxicity bioassays, we showed that fipronil, ivermectin and lotilaner are efficient pediculicides on adult lice. The RDL (Phh-RDL) and GluCl (Phh-GluCl) subunits were cloned and characterized by two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes. Phh-RDL and Phh-GluCl formed functional homomeric receptors respectively gated by GABA and L-glutamate with EC50 values of 16.0 μM and 9.3 μM. Importantly, ivermectin displayed a super agonist action on Phh-GluCl, whereas Phh-RDL receptors were weakly affected. Reversally, lotilaner strongly inhibited the GABA-evoked currents in Phh-RDL with an IC50 value of 40.7 nM, whereas it had no effect on Phh-GluCl. We report here for the first time the insecticidal activity of isoxazolines on human ectoparasites and reveal the mode of action of ivermectin and lotilaner on GluCl and RDL channels from human lice. These results emphasize an expected extension of the use of the isoxazoline drug class as new pediculicidal agents to tackle resistant-louse infestations in humans.

Highlights

Lice are spread throughout the world in both low- and high-income countries, with heterogenous prevalence depending on the geographical area [1,2]
We investigated the efficacy on lice of the classical macrocyclic lactone drug, ivermectin, and of the isoxazoline drug, lotilaner
We identified and pharmacologically characterized the first glutamate- and GABA-gated chloride channels ever described in human lice yet

Summary

Introduction

Lice are spread throughout the world in both low- and high-income countries, with heterogenous prevalence depending on the geographical area [1,2]. Even though silicon-based suffocating products are widely used nowadays, their efficacy largely depends on the respect of their application and is limited against the nits [13] Chemical insecticides such as organochloride (lindane), organophosphates (malathion), carbamates (carbaryl) and pyrethroids (pyrethrins and synthetic permethrin), which are the first line treatments recommended by the Centers for Disease Control and Prevention and by the American Academy of Pediatrics, have been widely used to control lice [14,15]. They have been proposed to inhibit γ-aminobutyric acid (GABA)-gated chloride channels, acetylcholinesterase and voltage-gated sodium channels, respectively, leading to the paralysis of the parasite.

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