Permethrin resistance in Aedes aegypti: Genomic variants that confer knockdown resistance, recovery, and death

Abstract

Pyrethroids are one of the few classes of insecticides available to control Aedes aegypti, the major vector of dengue, chikungunya, and Zika viruses. Unfortunately, evolving mechanisms of pyrethroid resistance in mosquito populations threaten our ability to control disease outbreaks. Two common pyrethroid resistance mechanisms occur in Ae. aegypti: 1) knockdown resistance, which involves amino acid substitutions at the pyrethroid target site—the voltage-gated sodium channel (VGSC)—and 2) enhanced metabolism by detoxification enzymes. When a heterogeneous population of mosquitoes is exposed to pyrethroids, different responses occur. During exposure, a proportion of mosquitoes exhibit immediate knockdown, whereas others are not knocked-down and are designated knockdown resistant (kdr). When these individuals are removed from the source of insecticide, the knocked-down mosquitoes can either remain in this status and lead to dead or recover within a few hours. The proportion of these phenotypic responses is dependent on the pyrethroid concentration and the genetic background of the population tested. In this study, we sequenced and performed pairwise genome comparisons between kdr, recovered, and dead phenotypes in a pyrethroid-resistant colony from Tapachula, Mexico. We identified single-nucleotide polymorphisms (SNPs) associated with each phenotype and identified genes that are likely associated with the mechanisms of pyrethroid resistance, including detoxification, the cuticle, and insecticide target sites. We identified high association between kdr and mutations at VGSC and moderate association with additional insecticide target site, detoxification, and cuticle protein coding genes. Recovery was associated with cuticle proteins, the voltage-dependent calcium channel, and a different group of detoxification genes. We provide a list of detoxification genes under directional selection in this field-resistant population. Their functional roles in pyrethroid metabolism and their potential uses as genomic markers of resistance require validation.

Genome-wide Association Study Reveals New Loci Associated With Pyrethroid Resistance in Aedes aegypti

“…aegypti may play an essential role in enhancing pyrethroid resistance, especially AAEL011338 in our populations. Still, other ankyrin genes may also be involved as indicated by the resistant mosquitoes from Mexico exhibiting enrichment for different ankyrin genes ( Campbell et al, 2019 ; Saavedra-Rodriguez et al, 2021 ). Since ankyrin is essential in microtubule dynamics ( Zhu et al, 2020 ) and synaptic stability ( Koch et al, 2008 ) in Drosophila , they could also be more directly implicated in resistance levels via structural changes in the synapse stability and neural activities.…”

“…There are several genes in this genome region, most with unknown functions. Other studies also pointed to several candidate genes involved in metabolic resistance or structural changes in the cuticle that could be correlated with increased resistance levels ( Campbell et al, 2019 ; Vera-Maloof et al, 2020 ; Saavedra-Rodriguez et al, 2021 ). All these genes may have an additive or synergistic effect with the kdr alleles on the overall resistance of a specific population, and studies relying only on one population may arrive at a large list of genes that may not be directly linked to pyrethroid resistance but rather reflect local adaptation or temporal variations.…”

“…Recent studies using single populations revealed the enrichment of several genes ( Campbell et al, 2019 ) or single nucleotide polymorphisms ( Saavedra-Rodriguez et al, 2021 ) in pyrethroid-resistant mosquitoes, indicating the involvement of other physiological selected mechanisms, which could be involved in increased detoxification of insecticides and cuticle impermeability, inhibiting insecticide penetrance. However, mosquitoes collected from the field may be exposed to different environmental chemicals that can potentially affect the expression levels of genes involved in detoxification processes.…”

Identification of SSTR5 Gene Polymorphisms and Their Association With Growth Traits in Hulun Buir Sheep

“…These types of mutations are often deleterious ( Saavedra-Rodriguez et al, 2021 ). In this study, SNP7 was identified as a non-synonymous mutation significantly associated with CaC at 9 months of age.…”

Isobaric tags for relative and absolute quantification-based proteomic analysis of host-pathogen protein interactions in the midgut of Aedes albopictus during dengue virus infection

“…PC protein, an important component of the periphagous membrane of insect intestines, is mosquito’s first natural barrier against the invasion of foreign microorganisms. Recent studies have shown the importance of reducing the penetration of insecticides into the stratum corneum as a mechanism of mosquito resistance ( Saavedra-Rodriguez and Campbell, 2021 ). For example, thickening of the cuticle was associated with reduced permeability to pyrethroids in resistant mosquitoes in Anopheles gambiae ( Yahouédo et al, 2017 ).…”