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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Metabolic and target-site mechanisms combine to confer strong DDT resistance in Anopheles gambiae
PLoS ONE, Volume 9, No. 3, Article e92662, Year 2014
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Description
The development of resistance to insecticides has become a classic exemplar of evolution occurring within human time scales. In this study we demonstrate how resistance to DDT in the major African malaria vector Anopheles gambiae is a result of both target-site resistance mechanisms that have introgressed between incipient species (the M- and S-molecular forms) and allelic variants in a DDT-detoxifying enzyme. Sequencing of the detoxification enzyme, Gste2, from DDT resistant and susceptible strains of An. gambiae, revealed a non-synonymous polymorphism (I114T), proximal to the DDT binding domain, which segregated with strain phenotype. Recombinant protein expression and DDT metabolism analysis revealed that the proteins from the susceptible strain lost activity at higher DDT concentrations, characteristic of substrate inhibition. The effect of I114T on GSTE2 protein structure was explored through X-ray crystallography. The amino acid exchange in the DDT-resistant strain introduced a hydroxyl group nearby the hydrophobic DDT-binding region. The exchange does not result in structural alterations but is predicted to facilitate local dynamics and enzyme activity. Expression of both wild-type and 114T alleles the allele in Drosophila conferred an increase in DDT tolerance. The 114T mutation was significantly associated with DDT resistance in wild caught M-form populations and acts in concert with target-site mutations in the voltage gated sodium channel (Vgsc-1575Y and Vgsc-1014F) to confer extreme levels of DDT resistance in wild caught An. gambiae. © 2014 Mitchell et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3968025/bin/pone.0092662.s001.docx
https://efashare.b-cdn.net/share/pmc/articles/PMC3968025/bin/pone.0092662.s002.csv
https://efashare.b-cdn.net/share/pmc/articles/PMC3968025/bin/pone.0092662.s003.csv
Authors & Co-Authors
Mitchell, Sara N.
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Rigden, Daniel John
United Kingdom, Liverpool
University of Liverpool
Dowd, Andrew J.
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Lu, Fang
United Kingdom, Liverpool
University of Liverpool
Wilding, Craig Stephen
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Weetman, David
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Dadzie, Samuel Kweku
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Jenkins, Adam M.
United States, Chestnut Hill
Boston College
Regna, Kimberly
United States, Chestnut Hill
Boston College
Boko, Pélagie Mimonnou
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Djogbenou, Salako Luc
Benin, Cotonou
University of Abomey-calavi
Muskavitch, Marc A.T.
United States, Chestnut Hill
Boston College
United States, Boston
Harvard T.h. Chan School of Public Health
Ranson, Hilary A.
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Paine, Mark John Ingraham
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
Mayans, Olga
United Kingdom, Liverpool
University of Liverpool
Donnelly, Martin J.
United Kingdom, Liverpool
Liverpool School of Tropical Medicine
United Kingdom, Hinxton
Wellcome Sanger Institute
Statistics
Citations: 111
Authors: 16
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0092662
e-ISSN:
19326203
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases
Noncommunicable Diseases