Mutations in GluCl associated with field ivermectin-resistant head lice from Senegal

Abstract

Through its unique mode of action, ivermectin represents a relatively new and very promising tool to fight against human lice, especially in cases of resistance to commonly used pediculicides. However, ivermectin resistance in the field has already begun to be reported. Therefore, understanding the mechanisms involved is a key step in delaying and tackling this phenomenon. In this study, field head lice with confirmed clinical resistance to ivermectin in rural human populations from Senegal were subjected to genetic analysis targeting the GluCl gene, the primary target of ivermectin known to be involved in resistance. Through DNA-polymorphism analysis, three relevant non-synonymous mutations in GluCl which were found only in ivermectin-resistant head lice (76 head lice tested), were identified. The A251V mutation found in the TM3 transmembrane domain was the most prevalent (allelic frequency of 0.33), followed by the S46P mutation (0.28) located at the N-terminal extracellular domain. The H272R was in the M3-M4 linker transmembrane region of GluCl and has shown the lowest frequency (0.18). Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) diagnostic assays were also developed for their accurate genotyping. Our study is the first to report the presence of GluCl point mutations in clinical ivermectin-resistant head lice occurring in rural human populations of Senegal.

Where Are We With Human Lice? A Review of the Current State of Knowledge

“…Genetic analysis of these lice by targeting GluCl gene, which is the primary target-site of ivermectin and already known to be implicated in resistance of arthropods and nematodes, revealed the presence of three relevant non-synonymous mutations (A251V, H272R, and S46P) that may be responsible for the treatment failure (Amanzougaghene et al, 2018a).…”

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

“…Wild, IVM-resistant pest isolates that express missense point mutations to GluClR subunits have been identified in the herbivorous species, Plutella xylostella [23, 24] (A30’V) and Tetranychus urticae [25–27] (G36’D, G36’E) and in a laboratory-induced mutation to a GluClR subunit of Drosophila melanogaster (P23’S) upon exposure to IVM [28] (Fig 1B). Point mutations to GluClR subunits are also being reported in human head lice, Pediculus humanus , that include the A55’V, and S46P and H272R, the latter two mutations being located in the extracellular and intracellular domains of the receptor, respectively [29].…”

The effects of insecticides on two splice variants of the glutamate‐gated chloride channel receptor of the major malaria vector, Anopheles gambiae

“…In particular, missense mutations to the M2–M3 linker and N‐terminal portion of the M3 domain confer IVM resistance in Tetranychus urticae (G36′D, G36′E; Kwon, Yoon, Clark, & Lee, ; Mermans, Dermauw, Geibel, & Van Leeuwen, ) and Plutella xylostella (A30′V; Wang et al, ), as well as in Drosophila melanogaster (P23′; Kane et al, ). A mutation just beyond the M3 (A55′V) has also been identified in the human head lice, Pediculus humanus (Amanzougaghene et al, ). However, all of these residues are conserved in the b1 and c subunits of A. gambiae (Figure a) and thus are unlikely to underlie the pharmacological difference between the two splice variants observed in this study.…”