Complexin in ivermectin resistance in body lice

Nadia Amanzougaghene (1) , Florence Fenollar (2) , Claude Nappez (2) , Amira Ben-Amara (1) , Philippe Decloquement (1) , Said Azza (1) , Yassina Bechah (2) , Eric Chabriere (1) , Didier Raoult (1) , Oleg Mediannikov (1, 3)

1 MEPHI - Microbes évolution phylogénie et infections
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 IRD - Institut de Recherche pour le Développement

Ivermectin has emerged as very promising pediculicide, particularly in cases of resistance to commonly used pediculicides. Recently, however, the first field-evolved ivermectin-resistance in lice was reported. To gain insight into the mechanisms underlying ivermectin-resistance, we both looked for mutations in the ivermectin-target site (GluCl) and searched the entire proteome for potential new loci involved in resistance from laboratory susceptible and ivermectin-selected resistant body lice. Polymorphism analysis of cDNA GluCl showed no non-silent mutations. Proteomic analysis identified 22 differentially regulated proteins, of which 13 were upregulated and 9 were downregulated in the resistant strain. We evaluated the correlation between mRNA and protein levels by qRT-PCR and found that the trend in transcriptional variation was consistent with the proteomic changes. Among differentially expressed proteins, a complexin i.e. a neuronal protein which plays a key role in regulating neurotransmitter release, was shown to be the most significantly down-expressed in the ivermectin-resistant lice. Moreover, DNA-mutation analysis revealed that some complexin transcripts from resistant lice gained a premature stop codon, suggesting that this down-expression might be due, in part, to secondary effects of a nonsense mutation inside the gene. We further confirmed the association between complexin and ivermectin-resistance by RNA-interfering and found that knocking down the complexin expression induces resistance to ivermectin in susceptible lice. Our results provide evidence that complexin plays a significant role in regulating ivermectin resistance in body lice and represents the first evidence that links complexin to insecticide resistance.

Mots clés: Transmembrane transport proteins; Proteomics; Protein expression; Cell binding; Binding analysis; RNA interference; Gene expression; Body lice

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]; Parasitologie

Nadia Amanzougaghene, Florence Fenollar, Claude Nappez, Amira Ben-Amara, Philippe Decloquement, et al.. Complexin in ivermectin resistance in body lice. PLoS Genetics, 2018, 14 (8), pp.e1007569. ⟨10.1371/journal.pgen.1007569⟩. ⟨hal-01924102⟩