Monitoring of pyrethroid resistance in <i>Aedes aegypti</i>: first report of double and triple <i>kdr</i> mutations in Buenos Aires Province

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Abstract

Background

Dengue is an emerging disease in Argentina due to the colonization of Aedes aegypti, the mosquito vector. Buenos Aires Province is the biggest and most populated district in Argentina, suffering dengue outbreaks of growing magnitude. During epidemic periods, pyrethroid insecticides are used in this country to control adult mosquitoes. Pyrethroid resistance in dengue vectors has been reported worldwide, making it necessary to implement resistance management strategies. The voltage-gated sodium channel is the target site of pyrethroids. Mutations in the gene encoding this protein, called kdr mutations, are usually the molecular cause of pyrethroid resistance in insects. In Ae. aegypti from the Americas, three kdr substitutions were described: V410L, V1016I, and F1534C. The diagnostic of kdr mutations is recommended for the early detection of pyrethroid resistance as well as the consequent planning of evidence-based control policies.

Methods

We distributed ovitraps across 16 localities in Buenos Aires Province, collecting 22,123 eggs. A total of 522 mosquitoes were genotyped in positions 1016 and 1534 of voltage-gated channel using multiplex high-resolution melting and/or TaqMan probe methods. A subset of 449 samples was also genotyped by a singleplex high-resolution melting method developed ad hoc and/or Sanger sequencing.

Results

We have documented, for the first time to our knowledge in the central region of Argentina, the presence of the 1016Ikdr + 1534Ckdr allele. Additionally, our study reports the first identification of the V410L mutation in central Argentina. These results underscore a growing trend of pyrethroid resistance in Ae. aegypti, fueled by the widespread use of these insecticides.

Conclusions

We detected 1016Ikdr + 1534Ckdr and 410Lkdr mutations in central Argentina for the first time and improved the processivity and accuracy of kdr genotyping methods. The results are both a tool for resistance monitoring and a sign of alarm to direct efforts towards finding sustainable methods for vector control to complement or replace pyrethroids. Joint efforts between academia and authorities to develop and implement public policies for vector control are a productive way to transfer scientific results for their application in public health.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s13071-024-06547-4.

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Most cited references 24

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Molecular biology of insect sodium channels and pyrethroid resistance.

Ke Dong, Yuzhe Du, Frank D Rinkevich … (2014)

Voltage-gated sodium channels are essential for the initiation and propagation of the action potential in neurons and other excitable cells. Because of their critical roles in electrical signaling, sodium channels are targets of a variety of naturally occurring and synthetic neurotoxins, including several classes of insecticides. This review is intended to provide an update on the molecular biology of insect sodium channels and the molecular mechanism of pyrethroid resistance. Although mammalian and insect sodium channels share fundamental topological and functional properties, most insect species carry only one sodium channel gene, compared to multiple sodium channel genes found in each mammalian species. Recent studies showed that two posttranscriptional mechanisms, alternative splicing and RNA editing, are involved in generating functional diversity of sodium channels in insects. More than 50 sodium channel mutations have been identified to be responsible for or associated with knockdown resistance (kdr) to pyrethroids in various arthropod pests and disease vectors. Elucidation of molecular mechanism of kdr led to the identification of dual receptor sites of pyrethroids on insect sodium channels. Many of the kdr mutations appear to be located within or close to the two receptor sites. The accumulating knowledge of insect sodium channels and their interactions with insecticides provides a foundation for understanding the neurophysiology of sodium channels in vivo and the development of new and safer insecticides for effective control of arthropod pests and human disease vectors.

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Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel.

Boris Zhorov, Crystal Y. Q. Du, Gul Satar … (2013)

Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and mosquito-borne diseases, including malaria and dengue. They exert toxic effects by altering the function of voltage-gated sodium channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of pyrethroids for vector control is the emergence of mosquito resistance to pyrethroids worldwide. Here, we report the successful expression of a sodium channel, AaNav1-1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine sodium channel mutations that are associated with pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNav1-1 sensitivity to pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed pyrethroid-receptor site in the house fly sodium channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of pyrethroid action and resistance as well as the high selectivity of pyrethroids on insect vs. mammalian sodium channels. Results from this study could impact future prediction and monitoring of pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.

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Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico

Farah Z. Vera-Maloof, Karla Saavedra-Rodriguez, Armando Elizondo-Quiroga … (2015)

Background Worldwide the mosquito Aedes aegypti (L.) is the principal urban vector of dengue viruses. Currently 2.5 billion people are at risk for infection and reduction of Ae. aegypti populations is the most effective means to reduce the risk of transmission. Pyrethroids are used extensively for adult mosquito control, especially during dengue outbreaks. Pyrethroids promote activation and prolong the activation of the voltage gated sodium channel protein (VGSC) by interacting with two distinct pyrethroid receptor sites [1], formed by the interfaces of the transmembrane helix subunit 6 (S6) of domains II and III. Mutations of S6 in domains II and III synergize so that double mutants have higher pyrethroid resistance than mutants in either domain alone. Computer models predict an allosteric interaction between mutations in the two domains. In Ae. aegypti, a Ile1,016 mutation in the S6 of domain II was discovered in 2006 and found to be associated with pyrethroid resistance in field populations in Mexico. In 2010 a second mutation, Cys1,534 in the S6 of domain III was discovered and also found to be associated with pyrethroid resistance and correlated with the frequency of Ile1,016. Methodology/Principal Findings A linkage disequilibrium analysis was performed on Ile1,016 and Cys1,534 in Ae. aegypti collected in Mexico from 2000–2012 to test for statistical associations between S6 in domains II and III in natural populations. We estimated the frequency of the four dilocus haplotypes in 1,016 and 1,534: Val1,016/Phe1,534 (susceptible), Val1,016/Cys1,534, Ile1,016/Phe1,534, and Ile1,016/Cys1,534 (resistant). The susceptible Val1,016/Phe1,534 haplotype went from near fixation to extinction and the resistant Ile1,016/Cys1,534 haplotype increased in all collections from a frequency close to zero to frequencies ranging from 0.5–0.9. The Val1,016/Cys1,534 haplotype increased in all collections until 2008 after which it began to decline as Ile1,016/Cys1,534 increased. However, the Ile1,016/Phe1,534 haplotype was rarely detected; it reached a frequency of only 0.09 in one collection and subsequently declined. Conclusion/Significance Pyrethroid resistance in the vgsc gene requires the sequential evolution of two mutations. The Ile1,016/Phe1,534 haplotype appears to have low fitness suggesting that Ile1,016 was unlikely to have evolved independently. Instead the Cys1,534 mutation evolved first but conferred only a low level of resistance. Ile1,016 in S6 of domain II then arose from the Val1,016/Cys1,534 haplotype and was rapidly selected because double mutants confer higher pyrethroid resistance. This pattern suggests that knowledge of the frequencies of mutations in both S6 in domains II and III are important to predict the potential of a population to evolve kdr. Susceptible populations with high Val1,016/Cys1,534 frequencies are at high risk for kdr evolution, whereas susceptible populations without either mutation are less likely to evolve high levels of kdr, at least over a 10 year period.

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Author and article information

Contributors

Mariana Manteca-Acosta: mantecaacosta@anlis.gob.ar

Sheila Ons: sheila.ons@presi.unlp.edu.ar

Journal

Journal ID (nlm-ta): Parasit Vectors

Journal ID (iso-abbrev): Parasit Vectors

Title: Parasites & Vectors

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-3305

Publication date (Electronic): 9 November 2024

Publication date PMC-release: 9 November 2024

Publication date Collection: 2024

Volume: 17

Electronic Location Identifier: 458

Affiliations

[1 ]Laboratorio de Neurobiología de Insectos (LNI), Centro Regional de Estudios Genómicos, Facultad de Ciencias Exactas, CENEXA, CONICET, Universidad Nacional de La Plata, ( https://ror.org/01tjs6929) La Plata, Buenos Aires Argentina

[2 ]GRID grid.452551.2, ISNI 0000 0001 2152 8611, Centro Nacional de Diagnóstico e Investigación en Endemo-Epidemias, CeNDIE, ANLIS Malbrán, Ministerio de Salud de la Nación, ; Buenos Aires, Argentina

[3 ]Laboratorio de Insectos Vectores, Centro de Estudios Parasitológicos y Vectores (CEPAVE CONICET CCT-La Plata-UNLP), La Plata, Buenos Aires Argentina

[4 ]Dirección de Salud Ambiental, Dirección Provincial de Epidemiología, Ministerio de Salud de la Provincia de Buenos Aires, ( https://ror.org/05evttw71) La Plata, Buenos Aires Argentina

Article

Publisher ID: 6547

DOI: 10.1186/s13071-024-06547-4

PMC ID: 11549831

SO-VID: 174a6ba1-07f9-43ce-8ac6-cafa7d8a842f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 July 2024

Date accepted : 18 October 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003285, Ministerio de Salud de la Nación;

Award ID: Salud Investiga 2022-2023

Award Recipient : Mariana Manteca-Acosta

Funded by: FundRef http://dx.doi.org/10.13039/501100021778, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación;

Award ID: PICT2020-0518

Award Recipient : Sheila Ons

Custom metadata

ScienceOpen disciplines: Parasitology

Keywords: dengue,mosquito,high-resolution melting,vector management,insecticide

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ScienceOpen disciplines: Parasitology

Keywords: dengue, mosquito, high-resolution melting, vector management, insecticide

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Monitoring of pyrethroid resistance in Aedes aegypti: first report of double and triple kdr mutations in Buenos Aires Province

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Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Supplementary Information

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Zika Virus

Most cited references 24

Molecular biology of insect sodium channels and pyrethroid resistance.

Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel.

Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico

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