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PLoS Negl Trop Dis
2019 Jun 03;136:e0007432. doi: 10.1371/journal.pntd.0007432.
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Molecular evidence of sequential evolution of DDT- and pyrethroid-resistant sodium channel in Aedes aegypti.
Chen M
,
Du Y
,
Wu S
,
Nomura Y
,
Zhu G
,
Zhorov BS
,
Dong K
.
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BACKGROUND: Multiple mutations in the voltage-gated sodium channel have been associated with knockdown resistance (kdr) to DDT and pyrethroid insecticides in a major human disease vector Aedes aegypti. One mutation, V1016G, confers sodium channel resistance to pyrethroids, but a different substitution in the same position V1016I alone had no effect. In pyrethroid-resistant Ae. aegypti populations, V1016I is often linked to another mutation, F1534C, which confers sodium channel resistance only to Type I pyrethroids including permethrin (PMT), but not to Type II pyrethroids including deltamethrin (DMT). Mosquitoes carrying both V1016G and F1534C exhibited a greater level of pyrethroid resistance than those carrying F1534C alone. More recently, a new mutation T1520I co-existing with F1534C was detected in India. However, whether V1016I or T1520I enhances pyrethroid resistance of sodium channels carrying F1534C remains unknown.
METHODOLOGY/PRINCIPAL FINDINGS: V1016I, V1016G, T1520I and F1534C substitutions were introduced alone and in various combinations into AaNav1-1, a sodium channel from Aedes aegypti. The mutant channels were then expressed in Xenopus oocytes and examined for channel properties and sensitivity to pyrethroids using the two-electrode voltage clamping technique. The results showed that V1016I or T1520I alone did not alter the AaNav1-1 sensitivity to PMT or DMT. However, the double mutant T1520I+F1534C was more resistant to PMT than F1534C, but remained sensitive to DMT. In contrast, the double mutant V1016I+F1534C was resistant to DMT and more resistant to PMT than F1534C. Furthermore, V1016I/G and F1534C channels, but not T1520I, were resistant to dichlorodiphenyltrichloroethane (DDT). Cryo-EM structures of sodium channels suggest that T1520I allosterically deforms geometry of the pyrethroid receptor site PyR1 in AaNav1-1. The small deformation does not affect binding of DDT, PMT or DMT, but in combination with F1534C it increases the channel resistance to PMT and DDT.
CONCLUSIONS/SIGNIFICANCE: Our data corroborated the previously proposed sequential selection of kdr mutations in Ae. aegypti. We proposed that mutation F1534C first emerged in response to DDT/pyrethroids providing a platform for subsequent selection of mutations V1016I and T1520I that confer greater and broader spectrum of pyrethroid resistance.
Fig 1. Gating properties of AaNav1-1 and V1016I channels.(A) Membrane topology. (B) Voltage dependence of activation. (C) Voltage dependence of fast inactivation. (D) Voltage dependence of slow inactivation. (E) Recovery from fast inactivation. (F) Recovery from slow inactivation. Voltage step protocols used to generate the curves are shown above each panel.
Fig 2. Gating properties of the AaNav1-1, T1520I and T1520I/F1534C channels.(A) Positions of T1520I and F1534C. (B) Voltage dependence of activation. (C) Voltage dependence of fast inactivation. (D) Voltage dependence of slow inactivation. (E) Recovery from fast inactivation. (F) Recovery from slow inactivation. Voltage step protocols are the same as in Fig 1.
Fig 6. (A) Sequence alignment of sodium channel segments involved in the proposed mechanism by which mutation T1520/3i(-1)I allosterically induces small changes in the PyR1 site geometry. Highlighted are residues (except position 2i18), which are shown in panels B and C. Residue numbers in NavPaS and EeNav1.4 are sequential numbers in the PDB files of the cryo-EM structures where some segments are lacking. (B) and (C), Cryo-EM structures of eukaryotic sodium channels NavPaS (B) and EeNav1.4 (C). The pore-module helices in repeats I, II, III, and IV are magenta, yellow, green and gray, respectively. Side chains in positions 2i18 and 3i13, which correspond to AaNav1-1 residues 1016 and 1534, are space-filled. In both channels, these residues are in the II/III repeat interface that harbors the pyrethroid receptor site PyR1. Threonine T3(i-1) in the extracellular loop of NavPaS, which correspond to T1520/3(i-1) in AaNav1-1, is close to the N-terminus of IIIS6 and in AaNav1-1 it cannot directly interact with PyR1-bound pyrethroids.
Fig 7. Sequential selection of kdr mutations for pyrethroid resistance in Ae. aegypti.Darker background colors indicate higher levels of resistance. V1016 and T1520I are selected in mosquitoes carrying F1534C. F1534C (and probably V1016I) emerged under the DDT pressure prior to usage of pyrethroids. T1520I was selected under pressure of Type I pyrethroids.
Al Nazawi,
Combined target site (kdr) mutations play a primary role in highly pyrethroid resistant phenotypes of Aedes aegypti from Saudi Arabia.
2017, Pubmed
Al Nazawi,
Combined target site (kdr) mutations play a primary role in highly pyrethroid resistant phenotypes of Aedes aegypti from Saudi Arabia.
2017,
Pubmed
Alvarez,
Frequency of V1016I and F1534C mutations in the voltage-gated sodium channel gene in Aedes aegypti in Venezuela.
2015,
Pubmed
Bloomquist,
Ion channels as targets for insecticides.
1996,
Pubmed
Bona,
Larval application of sodium channel homologous dsRNA restores pyrethroid insecticide susceptibility in a resistant adult mosquito population.
2016,
Pubmed
Brengues,
Pyrethroid and DDT cross-resistance in Aedes aegypti is correlated with novel mutations in the voltage-gated sodium channel gene.
2003,
Pubmed
Brito,
Levels of Resistance to Pyrethroid among Distinct kdr Alleles in Aedes aegypti Laboratory Lines and Frequency of kdr Alleles in 27 Natural Populations from Rio de Janeiro, Brazil.
2018,
Pubmed
Catterall,
Voltage-gated sodium channels at 60: structure, function and pathophysiology.
2012,
Pubmed
Chang,
A novel amino acid substitution in a voltage-gated sodium channel is associated with knockdown resistance to permethrin in Aedes aegypti.
2009,
Pubmed
Cornel,
Surveillance, insecticide resistance and control of an invasive Aedes aegypti (Diptera: Culicidae) population in California.
2016,
Pubmed
Dong,
Molecular biology of insect sodium channels and pyrethroid resistance.
2014,
Pubmed
Du,
Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel.
2013,
Pubmed
,
Xenbase
Du,
Rotational Symmetry of Two Pyrethroid Receptor Sites in the Mosquito Sodium Channel.
2015,
Pubmed
Du,
Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels.
2016,
Pubmed
Feng,
Cloning and functional analysis of TipE, a novel membrane protein that enhances Drosophila para sodium channel function.
1995,
Pubmed
,
Xenbase
Goldin,
Mechanisms of sodium channel inactivation.
2003,
Pubmed
Granada,
A Point Mutation V419L in the Sodium Channel Gene from Natural Populations of Aedes aegypti Is Involved in Resistance to λ-Cyhalothrin in Colombia.
2018,
Pubmed
Grossman,
Fine-scale spatial and temporal dynamics of kdr haplotypes in Aedes aegypti from Mexico.
2019,
Pubmed
Haddi,
Detection of a new pyrethroid resistance mutation (V410L) in the sodium channel of Aedes aegypti: a potential challenge for mosquito control.
2017,
Pubmed
,
Xenbase
Harris,
Pyrethroid resistance in Aedes aegypti from Grand Cayman.
2010,
Pubmed
HURLBUT,
DDT resistance in Korean body lice.
1952,
Pubmed
Ishak,
Contrasting patterns of insecticide resistance and knockdown resistance (kdr) in the dengue vectors Aedes aegypti and Aedes albopictus from Malaysia.
2015,
Pubmed
Jones,
Footprints of positive selection associated with a mutation (N1575Y) in the voltage-gated sodium channel of Anopheles gambiae.
2012,
Pubmed
Kawada,
Co-occurrence of point mutations in the voltage-gated sodium channel of pyrethroid-resistant Aedes aegypti populations in Myanmar.
2014,
Pubmed
Kawada,
Widespread distribution of a newly found point mutation in voltage-gated sodium channel in pyrethroid-resistant Aedes aegypti populations in Vietnam.
2009,
Pubmed
Kushwah,
Pyrethroid-resistance and presence of two knockdown resistance (kdr) mutations, F1534C and a novel mutation T1520I, in Indian Aedes aegypti.
2015,
Pubmed
Linss,
Distribution and dissemination of the Val1016Ile and Phe1534Cys Kdr mutations in Aedes aegypti Brazilian natural populations.
2014,
Pubmed
Liu,
Synergistic interaction between two cockroach sodium channel mutations and a tobacco budworm sodium channel mutation in reducing channel sensitivity to a pyrethroid insecticide.
2002,
Pubmed
López-Carrillo,
Is DDT use a public health problem in Mexico?
1996,
Pubmed
Maestre-Serrano,
Co-occurrence of V1016I and F1534C mutations in the voltage-gated sodium channel and resistance to pyrethroids in Aedes aegypti (L.) from the Colombian Caribbean region.
2019,
Pubmed
Nájera,
Some lessons for the future from the Global Malaria Eradication Programme (1955-1969).
2011,
Pubmed
Narahashi,
Neuroreceptors and ion channels as the basis for drug action: past, present, and future.
2000,
Pubmed
Narahashi,
Sodium and GABA-activated channels as the targets of pyrethroids and cyclodienes.
1992,
Pubmed
Pang,
Low efficacy of delthamethrin-treated net against Singapore Aedes aegypti is associated with kdr-type resistance.
2015,
Pubmed
Plernsub,
Temporal frequency of knockdown resistance mutations, F1534C and V1016G, in Aedes aegypti in Chiang Mai city, Thailand and the impact of the mutations on the efficiency of thermal fogging spray with pyrethroids.
2016,
Pubmed
Rajatileka,
Development and application of a simple colorimetric assay reveals widespread distribution of sodium channel mutations in Thai populations of Aedes aegypti.
2008,
Pubmed
Ranson,
Insecticide Resistance in African Anopheles Mosquitoes: A Worsening Situation that Needs Urgent Action to Maintain Malaria Control.
2016,
Pubmed
Saavedra-Rodriguez,
A mutation in the voltage-gated sodium channel gene associated with pyrethroid resistance in Latin American Aedes aegypti.
2007,
Pubmed
Saavedra-Rodriguez,
Parallel evolution of vgsc mutations at domains IS6, IIS6 and IIIS6 in pyrethroid resistant Aedes aegypti from Mexico.
2018,
Pubmed
Shen,
Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution.
2017,
Pubmed
Soderlund,
State-Dependent Modification of Voltage-Gated Sodium Channels by Pyrethroids.
2010,
Pubmed
,
Xenbase
Soderlund,
Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances.
2012,
Pubmed
Srisawat,
Field-collected permethrin-resistant Aedes aegypti from central Thailand contain point mutations in the domain IIS6 of the sodium channel gene (KDR).
2012,
Pubmed
Stenhouse,
Detection of the V1016G mutation in the voltage-gated sodium channel gene of Aedes aegypti (Diptera: Culicidae) by allele-specific PCR assay, and its distribution and effect on deltamethrin resistance in Thailand.
2013,
Pubmed
Sula,
The complete structure of an activated open sodium channel.
2017,
Pubmed
Tan,
Identification of amino acid residues in the insect sodium channel critical for pyrethroid binding.
2005,
Pubmed
,
Xenbase
Tatebayashi,
Differential mechanism of action of the pyrethroid tetramethrin on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels.
1994,
Pubmed
Vais,
A single amino acid change makes a rat neuronal sodium channel highly sensitive to pyrethroid insecticides.
2000,
Pubmed
,
Xenbase
Vera-Maloof,
Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico.
2015,
Pubmed
Vijverberg,
Annotation. Action of pyrethroid insecticides on the vertebrate nervous system.
1982,
Pubmed
Wang,
A mutation in the intracellular loop III/IV of mosquito sodium channel synergizes the effect of mutations in helix IIS6 on pyrethroid resistance.
2015,
Pubmed
,
Xenbase
Warmke,
Functional expression of Drosophila para sodium channels. Modulation by the membrane protein TipE and toxin pharmacology.
1997,
Pubmed
,
Xenbase
Wu,
Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate.
2017,
Pubmed
,
Xenbase
Yan,
Structure of the Nav1.4-β1 Complex from Electric Eel.
2017,
Pubmed
Zhorov,
Potassium, sodium, calcium and glutamate-gated channels: pore architecture and ligand action.
2004,
Pubmed
