Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti
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Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated sodium channels are the primary targets of pyrethroid insecticides. Mutations in the sodium channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr), in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the sodium channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated sodium channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the sodium channel.Keywords:
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Background Resistance of Aedes aegypti to photostable pyrethroid insecticides is a major problem for disease-vector control programs. Pyrethroids target the voltage-gated sodium channel on the insects' neurons. Single amino acid substitutions in this channel associated with pyrethroid resistance are one of the main factors that cause knockdown resistance in insects. Although kdr has been observed in several mosquito species, point mutations in the para gene have not been fully characterized in Ae. aegypti populations in Vietnam. The aim of this study was to determine the types and frequencies of mutations in the para gene in Ae. aegypti collected from used tires in Vietnam. Methods and Findings Several point mutations were examined that cause insensitivity of the voltage-gated sodium channel in the insect nervous system due to the replacement of the amino acids L1014F, the most commonly found point mutation in several mosquitoes; I1011M (or V) and V1016G (or I), which have been reported to be associated to knockdown resistance in Ae. aegypti located in segment 6, domain II; and a recently found amino acid replacement in F1269 in Ae. aegypti, located in segment 6, domain III. Among 756 larvae from 70 locations, no I1011M or I1011V nor L1014F mutations were found, and only two heterozygous V1016G mosquitoes were detected. However, F1269C mutations on domain III were distributed widely and with high frequency in 269 individuals among 757 larvae (53 collection sites among 70 locations surveyed). F1269C frequencies were low in the middle to north part of Vietnam but were high in the areas neighboring big cities and in the south of Vietnam, with the exception of the southern mountainous areas located at an elevation of 500–1000 m. Conclusions The overall percentage of homozygous F1269C seems to remain low (7.4%) in the present situation. However, extensive and uncontrolled frequent use of photostable pyrethroids might be a strong selection pressure for this mutation to cause serious problems in the control of dengue fever in Vietnam.
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Voltage-gated sodium channels are the primary target of pyrethroid insecticides. Mutations in sodium channel confer knockdown resistance (kdr) to pyrethroids in various arthropod pests. Haedoxan A (HA) is the major insecticidal component from Phryma leptostachya. It has been shown that HA alters electrical responses at the Drosophila neuromuscular junction and modifies the gating properties of cockroach sodium channels expressed in Xenopus oocytes. However, whether sodium channel mutations that confer pyrethroid resistance also affect the action of HA is unknown. In this study, we conducted bioassays using HA and permethrin in two Drosophila melanogaster strains: w1118 , an insecticide-susceptible strain, and parats1 , a pyrethroid-resistant strain due to a I265N mutation in the sodium channel, and identified a new case of negative cross-resistance (NCR) between permethrin and HA. Both parats1 larvae and adults were more resistant to permethrin, as expected. However, both parats1 larvae and adults were more sensitive to HA compared to w1118 . We confirmed that the I265N mutation reduced the sensitivity to permethrin of a Drosophila sodium channel variant, DmNav 22, expressed in Xenopus oocytes. Interestingly, the I265N mutation also abolished the effect of HA on sodium channels. Further characterization showed that I265 on the sodium channels is critical for the action of both pyrethroids and HA on sodium channels, pointing to an overlapping mode of action between pyrethroids and HA on the sodium channel. Overall, our results suggest an I265N-independnt mechanism(s) in parats1 flies that is responsible for the NCR between permethrin and HA at the whole insect level.
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Four novel commercial insecticide mixtures, composed of pyrethroid and nicotinoid active ingredients, were evaluated in a series of experiments in the laboratory, semi-field and field to determine acute toxicity (LC50) against pyrethroid-susceptible (ORL1952) and resistant (Puerto Rico) strains of Aedes aegypti L., and non-target adult European honey bees, Apis mellifera L. The four products were Tandem, Temprid FX, Transport Mikron, and Crossfire. The acute toxicity data showed that pyrethroid-resistant Ae. aegypti PR exhibited decreased sensitivity to all 4 insecticide mixtures, compared to pyrethroid-susceptible Ae. aegypti ORL1952. Tandem, Temprid FX, and Transport Mikron were more toxic to Ae. aegypti ORL1952 than to A. mellifera, but Crossfire was the least toxic. Transport Mikron was also more toxic to Ae. aegypti PR than to A. mellifera. The Honey bee Tolerance Indexes, determined with LC50 data of pyrethroid-susceptible mosquitoes, demonstrated that while Transport Mikron, Tandem, and Temprid FX were more toxic to Ae. aegypti ORL1952 than to A. mellifera, Crossfire was less toxic. The honey bee Tolerance Indexes decreased substantially when calculated with LC50 data from pyrethroid- resistant mosquitoes, but honey bees remained tolerant of Transport Mikron. Notably, while the insecticide mixtures did not control the PR resistant Ae. aegypti strain when applied as residual sprays to perimeter vegetation at label rates, susceptible Ae. aegypti ORL1951 were controlled, but applications affected honeybees (A. mellifera) for up to 28 days after treatment. Temprid FX resulted in 74% and 99% mortality, in adult Ae. aegypti ORL1952 and A. mellifera, respectively, for 28 days post-treatment. Transport Mikron and Tandem residues killed Ae. aegypti ORL1952 for up to 21 days post-treatment, while the effect of Crossfire lasted only 14 days. All three insecticides killed A. mellifera for up to 28 days post-treatment but at decreased mortality rates. For operational mosquito control, these data indicate that Transport Mikron has a reasonable safety margin (~25%) when targeting susceptible mosquitoes, compared to Tandem, Temprid FX, and Crossfire. The tested insecticide formulations need to be applied in higher doses to control resistant strains of mosquitoes that may be detrimental to honey bees. The ULV data indicated that pyrethroid resistance can be overcome with the insecticide mixtures.
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Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated sodium channels are the primary targets of pyrethroid insecticides. Mutations in the sodium channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr), in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the sodium channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated sodium channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the sodium channel.
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Aedes aegypti is the primary mosquito vector of dengue, yellow fever, Zika and chikungunya. Current strategies to control Ae. aegypti rely heavily on insecticide interventions. Pyrethroids are a major class of insecticides used for mosquito control because of their fast acting, highly insecticidal activities and low mammalian toxicity. However, Ae. aegypti populations around the world have begun to develop resistance to pyrethroids. So far, more than a dozen mutations in the sodium channel gene have been reported to be associated with pyrethroid resistance in Ae. aegypti. Co-occurrence of resistance-associated mutations is common in pyrethroid-resistant Ae. aegypti populations. As global use of pyrethroids in mosquito control continues, new pyrethroid-resistant mutations keep emerging. In this microreview, we compile pyrethroid resistance-associated mutations in Ae. aegypti in a chronological order, as they were reported, and summarize findings from functional evaluation of these mutations in an in vitro sodium channel expression system. We hope that the information will be useful for tracing possible evolution of pyrethroid resistance in this important human disease vector, in addition to the development of methods for global monitoring and management of pyrethroid resistance in Ae. aegypti.
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