Imperial College London
Alternate

DrTonyNolan

Faculty of Natural Sciences, Department of Life Sciences

Honorary Senior Lecturer
 
 
 
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Contact

 

t.nolan

 
 
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Assistant

 

Mrs Lucy Collyns +44 (0)20 7594 5395

 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Grigoraki:2021:10.1101/2021.04.20.440595,
author = {Grigoraki, L and Cowlishaw, R and Nolan, T and Donnelly, M and Lycett, G and Ranson, H},
doi = {10.1101/2021.04.20.440595},
title = {CRISPR/Cas9 modified<i>An. gambiae</i>carrying kdr mutation L1014F functionally validate its contribution in insecticide resistance and interaction with metabolic enzymes},
url = {http://dx.doi.org/10.1101/2021.04.20.440595},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>Insecticide resistance in<jats:italic>Anopheles</jats:italic>mosquitoes is a major obstacle in maintaining the momentum in reducing the malaria burden; mitigating strategies require improved understanding of the underlying mechanisms. Mutations in the target site of insecticides (the voltage gated sodium channel for the most widely used pyrethroid class) and over-expression of detoxification enzymes are commonly reported, but their relative contribution to phenotypic resistance remain poorly understood. Here we present a genome editing pipeline to introduce single nucleotide polymorphisms in<jats:italic>An. gambiae</jats:italic>which we have used to study the effect of the classical kdr mutation L1014F (L995F based on<jats:italic>An. gambiae</jats:italic>numbering), one of the most widely distributed resistance alleles. Introduction of 1014F in an otherwise fully susceptible genetic background increased levels of resistance to all tested pyrethroids and DDT ranging from 9.9-fold for permethrin to >24-fold for DDT. The introduction of the 1014F allele was sufficient to reduce mortality of mosquitoes after exposure to deltamethrin treated bednets, even as the only resistance mechanism present. When 1014F was combined with over-expression of glutathione transferase Gste2, resistance to permethrin increased further demonstrating the critical combined effect between target site resistance and detoxification enzymes<jats:italic>in vivo</jats:italic>. We also show that mosquitoes carrying the 1014F allele in homozygosity showed fitness disadvantages including increased mortality at the larval stage and a reduction in fecundity and adult longevity, which can have consequences for the strength of selection that will apply to this allele in the field.</jats:p><jats:sec><jats:title>Author Summary</jats:title><jats:p>Escalation of pyret
AU  - Grigoraki,L
AU  - Cowlishaw,R
AU  - Nolan,T
AU  - Donnelly,M
AU  - Lycett,G
AU  - Ranson,H
DO  - 10.1101/2021.04.20.440595
PY  - 2021///
TI  - CRISPR/Cas9 modified<i>An. gambiae</i>carrying kdr mutation L1014F functionally validate its contribution in insecticide resistance and interaction with metabolic enzymes
UR  - http://dx.doi.org/10.1101/2021.04.20.440595
ER  -
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