@conference {96346, title = {The Effect of Insecticides on GABA Receptors of Human Louse Pediculus humanus (poster)}, booktitle = {15th The international conference of parasitology (ICOPA}, year = {2022}, month = {Aug 2022}, address = {Copenhagen - Denmark}, abstract = {

Poster at the Conference

}, url = {https://www.researchgate.net/publication/363310671_The_Effect_of_Insecticides_on_GABA_Receptors_of_Human_Louse_Pediculus_humanus}, author = {Omar Hashim and Claude L. Charvet and Toubate, Berthine and Aimun A. E. Ahmed and C{\'e}dric Neveu and Isabelle Dimier-Poisson and Fran{\c c}oise Debierre-Grockiego and Catherine Dupuy} } @conference {96345, title = {Molecular Cloning, Functional Characterization and Spatiotemporal Expression of GABA Receptor Subunits from Human Body Louse Pediculus humanus humanus}, booktitle = {8th European Congress of Pharmacology (EPHAR 2021)}, year = {2021}, month = {Dec-2021}, address = {Prague, Czech Republic}, abstract = {

A conference presentation

Abstract: Human body louse Pediculus humanus humanus is a cosmopolitan obligatory blood feeding ectoparasite, a known vector of Riketsia brawazaki, Borellia recurrentis and Bartonella quintana transmitting epidemic typhus, recurrent fever and the louse borne relapsing fever respectively. GABA receptors are traditional targets for parasiticides and insecticides, four subunits of GABA were characterized in insects; RDL, LCCH3, GRD and GC8916. The commonly used pediculicides were either resisted by emerging strains or prohibited due to high toxicity to man and environment. The homopentameric receptor constituted by PhhRDL was already described, in this article, we cloned and characterized three variants of PhhGRD, one variant of Phh8916 and one variant of PhhLCCH3, the functional expression in xenopus oocytes and the pharmacology of receptors constituted by these GABA subunits were assayed using two electrode voltage clamp(TEVC). To our knowledge, this is the first functional expression of 8916 in insects. Furthermore the relative expressions of PhhGRD, Phh8916, PhhLCCH3 and PhhRDL were predicted by quantitative real time PCR(RT-qPCR). These findings provided valuable additions to our knowledge of the complex nature of GABA receptor in human body louse that could help in understanding the resistance pattern to commonly used pediculicides and to develop new effective and selective molecules.

}, url = {https://www.researchgate.net/publication/362191070_Molecular_Cloning_Functional_Characterization_and_Spatiotemporal_Expression_of_GABA_Receptor_Subunits_from_Human_Body_Louse_Pediculus_humanus_humanus}, author = {Omar Hashim and Claude L. Charvet and Toubate, Berthine and Aimun A. E. Ahmed and C{\'e}dric Neveu and Isabelle Dimier-Poisson and Fran{\c c}oise Debierre-Grockiego and Catherine Dupuy} } @article {96344, title = {Molecular and Functional Characterization of GABA Receptor Subunits GRD and LCCH3 from Human Louse Pediculus Humanus Humanus}, journal = {Molecular Pharmacology}, volume = {102}, year = {2022}, month = {Aug-2022}, pages = {116-127}, abstract = {

Human louse Pediculus humanus is a cosmopolitan obligatory blood-feeding ectoparasite causing pediculosis and transmitting many bacterial pathogens. Control of infestation is difficult due to the developed resistance to insecticides that mainly target GABA (\γ-aminobutyric acid) receptors. Previous work showed that Pediculus humanus humanus (Phh) GABA receptor subunit resistance to dieldrin (RDL) is the target of lotilaner, a synthetic molecule of the isoxazoline chemical class. To enhance our understanding of how insecticides act on GABA receptors, two other GABA receptor subunits were cloned and characterized: three variants of Phh-grd (glycine-like receptor of Drosophila) and one variant of Phh-lcch3 (ligand-gated chloride channel homolog 3). Relative mRNA expression levels of Phh-rdl, Phh-grd, and Phh-lcch3 revealed that they were expressed throughout the developmental stages (eggs, larvae, adults) and in the different parts of adult lice (head, thorax, and abdomen). When expressed individually in the Xenopus oocyte heterologous expression system, Phh-GRD1, Phh-GRD2, Phh-GRD3, and Phh-LCCH3 were unable to reconstitute functional channels, whereas the subunit combinations Phh-GRD1/Phh-LCCH3, Phh-GRD1/Phh-RDL, and Phh-LCCH3/Phh-RDL responded to GABA in a concentration-dependent manner. The three heteromeric receptors were similarly sensitive to the antagonistic effect of picrotoxin and fipronil, whereas Phh-GRD1/Phh-RDL and Phh-LCCH3/Phh-RDL were respectively about 2.5-fold and 5-fold more sensitive to ivermectin than Phh-GRD1/Phh-LCCH3. Moreover, the heteropentameric receptor constituted by Phh-GRD1/Phh-LCCH3 was found to be permeable and highly sensitive to the extracellular sodium concentration. These findings provided valuable additions to our knowledge of the complex nature of GABA receptors in human louse that could help in understanding the resistance pattern to commonly used pediculicides.

SIGNIFICANCE STATEMENT: Human louse is an ectoparasite that causes pediculosis and transmits several bacterial pathogens. Emerging strains developed resistance to the commonly used insecticides, especially those targeting GABA receptors. To understand the molecular mechanisms underlying this resistance, two subunits of GABA receptors were cloned and described: Phh-grd and Phh-lcch3. The heteromeric receptor reconstituted with the two subunits was functional in Xenopus oocytes and sensitive to commercially available insecticides. Moreover, both subunits were transcribed throughout the parasite lifecycle.

}, issn = {0026-895X, 1521-0111}, doi = {10.1124/molpharm.122.000499}, url = {https://molpharm.aspetjournals.org/content/102/2/116}, author = {Omar Hashim and Claude L. Charvet and Toubate, Berthine and Aimun A. E. Ahmed and Nicolas Lamassiaude and C{\'e}dric Neveu and Isabelle Dimier-Poisson and Fran{\c c}oise Debierre-Grockiego and Catherine Dupuy} } @article {96076, title = {The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis}, journal = {PLoS Pathogens}, volume = {17}, year = {2021}, month = {Feb-18-2021}, pages = {25 pp}, type = {Open Access}, 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 theresistant todieldrin (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 speciesPediculus 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 inXenopus laevisoocytes. Phh-RDL and Phh-GluCl formed functional homomeric receptors respectively gated by GABA and L-glutamate with EC50values 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 IC50value 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.

Author summary
Human cosmopolitan lice are responsible for pediculosis, which represent a significant public health concern. Resistant lice against insecticides and lack of safety of the treatments for human and environment is a growing issue worldwide. Here we investigated the efficacy on lice of the classical macrocyclic lactone drug, ivermectin, and of the isoxzoline drug, lotilaner. This study was done to decipher their mode of action at the molecular and functional levels in order to propose new strategies to control lice infestation. Our
bioassay results indicate that ivermectin and lotilaner were potent at killing human adult lice, with lotilaner showing a higher efficacy than ivermectin. Furthermore, we identified and pharmacologically characterized the first glutamate- and GABA-gated chloride chan-
nels ever described in human lice yet. Mechanistically, our molecular biology and electrophysiology findings demonstrate that ivermectin acted preferentially at glutamate channels, while lotilaner specifically targeted GABA channels. These results provide new
insights in the understanding of the insecticide mode of action and highlight the potential of isoxazolines as a new alternative for the treatment of human lice.

}, issn = {1553-7374}, doi = {10.1371/journal.ppat.1008863}, url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008863}, author = {Nicolas Lamassiaude and Toubate, Berthine and C{\'e}dric Neveu and Pierre Charnet and Catherine Dupuy and Fran{\c c}oise Debierre-Grockiego and Isabelle Dimier-Poisson and Claude L. Charvet} } @article {68948, title = {Ex vivo effectiveness of French over-the-counter products against head lice (Pediculus humanus capitis De Geer, 1778)}, journal = {Parasitology Research}, volume = {114}, year = {2015}, month = {Jan-05-2015}, pages = {1779 - 1792}, abstract = {

Head lice infestation is still a public health problem worldwide, with an intracountry and intercountry prevalence \ ariation of 0.7 to 59\%. There is a large variety of over-the-counter anti-louse products, but their efficacy is not \ lways well assessed. Our objective was to test the pediculicidal and ovicidal efficacy of 21 over-the-counter head louse products, available in France during the period of 2008 to 2012. We tested children living in Tours City in central France and visiting preschools, primary schools, kindergarten, camps, and child care facilities, as well as children in their family houses, and were examined for the presence of lice. The products were collected from randomly selected pharmacies by covert investigators and then tested in the laboratory on an ex vivo sample of head lice and their eggs, collected from the hair of infested children. Living lice and unharmed eggs were \ collected from the scalps of 3-12 years old. The laboratory conditions for ex vivo testing mimicked the manufacturers\&$\#$39; instructions for exposure time and application method. In 21 runs, 3919 living lice and 4321 undamaged living eggs were collected from the scalp of over 400 children. The 21 products were classified in three groups: 6 products in a group of potentially 100\% pediculicidal activity and potentially 100\% ovicidal activity, 8 products in a group of potentially 100\% pediculicidal activity but insufficient ovicidal activity (including 2 products with claims of single application treatment), and 7 products in a group of insufficient pediculicidal activity and ovicidal activity. The pharmaceutical market for head lice products in France is swamped with poorly tested and ineffective products. Rigorous efficacy testing preregistration and periodic screening and testing of \ ffectiveness in the post-registration period should be endorsed by the health authorities.

}, keywords = {Effectiveness, Ex vivo assays, France}, issn = {0932-0113}, doi = {10.1007/s00436-015-4363-9}, url = {http://phthiraptera.info/sites/phthiraptera.info/files/68948.pdf}, author = {Combescot-Lang, Catherine and Vander Stichele,Robert H. and Toubate, Berthine and Veirron, Emilie and Kosta Y. Mumcuoglu} }