Emergence of hyper insecticide-resistant dengue vectors in Indochina Peninsula: threats of concomitant knockdown resistance mutations

Abstract

AbstractAedes aegypti(Linnaeus, 1762) is the main mosquito vector for dengue and other arboviral infectious diseases. Control of this important vector highly relies on the use of insecticides, especially pyrethroids. Nevertheless, the development of pyrethroid resistance is a major obstacle to mosquito/disease control worldwide. Here, we focused on the mutations in the target site of pyrethroid insecticides, voltage-sensitive sodium channel (Vssc), and found thatAe. aegypticollected from Vietnam has the L982W allele in theVsscat a high frequency (>79%). L982W mutation is located in the highly conserved region ofVsscthat is associated with sodium–ion selectivity and permeation rate. Strains having the L982W allele showed similar or even higher levels of resistance to pyrethroids than those having V1016G, a typical knockdown resistance allele in Asia. Furthermore, concomitant mutations L982W+F1534C and V1016G+F1534C were confirmed, and strains having these multipleVsscmutations exhibited incomparably higher levels of pyrethroid resistance than any other field population ever reported. Molecular modeling analysis confirmed that these concomitant mutant alleles could interfere with approaching pyrethroid toVssc. Remarkably, >90% ofVsscofAe. aegyptiwere occupied by these hyper insecticide-resistant haplotypes in Phnom Penh city, Cambodia. Analysis of wholeVssccoding genes suggested thatVsscs have evolved into stronger resistant forms efficiently through gene recombination events. At this point, L982W has never been detected inVsscofAe. aegyptifrom any other neighboring countries. We strongly emphasize the need to be vigilant about these strong resistance genes spreading to the world through Indochina Peninsula.Significance StatementThe high frequency (>78%) of the L982W allele was detected at the target site of the pyrethroid insecticide, the voltage-sensitive sodium channel (Vssc) ofAedes aegypticollected from Vietnam and Cambodia. Haplotypes having concomitant mutations L982W+F1534C and V1016G+F1534C were also confirmed in both countries, and their frequency was high (>90%) in Phnom Penh, Cambodia. Strains having these haplotypes exhibited substantially higher levels of pyrethroid resistance than any other field population ever reported. The L982W mutation has never been detected in any country of the Indochina Peninsula except Vietnam and Cambodia, but it may be spreading to other areas of Asia, which can cause an unprecedentedly serious threat to the control of dengue fever as well as otherAedes-borne infectious diseases.