Down-regulation of complexin is associated with ivermectin resistance in body lice

Lice (Anoplura) are obligate blood-feeding ectoparasites of mammals; humans are the preferred host for at least two species –– Pthirus pubis and Pediculus humanus. The latter has significant relevance to public health, including head lice (living in the hair) and body lice (living in clothing). Body lice are associated with poor socio-economic conditions, homeless people, and refugee-camp populations. Body lice are the main vectors of at least three serious pathogenic bacteria, namely: Rickettsia prowazekii (causing epidemic typhus), Bartonella quintana (causing trench fever), and Borrelia recurrentis (causing relapsing fever). Prevalence of the body louse is underestimated in many developed countries and, as the number of homeless people increases, louse-borne infectious diseases are also on the rise. Recently, more emphasis has been placed on the ability of head lice to transmit bacterial diseases. The DNA of three pathogenic bacteria is being increasingly detected in head lice –– including B. quintana, B. recurrentis and Yersinia pestis (causing plague).

Infected head lice are capable of acquiring, maintaining and transmitting R. prowazekii and B. quintana –– demonstrating that these lice have the potential to be a vector of pathogens. These facts may pose a very substantial threat to humanity, because such infestations are not controlled in any country, including developed countries, despite repeated efforts to eradicate them. This is mainly due to the resistance developed by lice to widely-used insecticides such as malathion and pyrethroid. The use of new effective products with different modes of action, such as ivermectin, have proven to be a promising alternative to combatting the problem of resistance.

To gain insight into the mechanisms underlying ivermectin-resistance, authors [see attached report] both looked for mutations in the ivermectin-target site (glutamate-gated chloride channel; GluCl) and searched the entire proteome for potential new loci involved in resistance from laboratory-susceptible and ivermectin-selected-resistant body lice. Proteomic analysis identified 22 differentially regulated proteins, of which 13 were up-regulated and 9 were down-regulated in the resistant strain. They showed that the trends in transcriptional variation (messenger-RNA formation) were consistent with the proteomic changes.

Among differentially expressed proteins, a complexin (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. Complexin (also known as synaphin; encoded by the CPLX1-CPLX2-CPLX3-CPLX4 genes) refers to any of four cytoplasmic neuronal proteins which bind to the SNARE protein complex (consisting of at least 24 proteins in yeast, more than 60 in mammalian cells, and who knows how many in body lice). These [gene-environment interactions (GxE)] data provide evidence that complexin plays a significant role in regulating ivermectin resistance in body lice. These results represent the first evidence that links complexin to insecticide resistance.


PloS Genet Aug 2o18; 14: e1007569

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