In vivo functional validation of the V402L voltage gated sodium channel mutation in the malaria vector An. gambiae

Williams, Jessica, Cowlishaw, Ruth, Sanou, Antoine, Ranson, Hilary ORCID: https://orcid.org/0000-0003-2332-8247 and Grigoraki, Linta ORCID: https://orcid.org/0000-0001-8997-0406 (2021) 'In vivo functional validation of the V402L voltage gated sodium channel mutation in the malaria vector An. gambiae'. Pest Management Science, Vol 78, Issue 3, pp. 1155-1163.

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Abstract

BACKGROUND
Pyrethroids are the most widely used insecticides for the control of malaria transmitting Anopheles gambiae mosquitoes and rapid increase in resistance to this insecticide class is of major concern. Pyrethroids target the Voltage Gated Sodium Channels (VGSCs), that have a key role in the normal function of the mosquitoes' nervous system. VGSC mutations L995F and L995S have long been associated with pyrethroid resistance and screening for their presence is routine in insecticide resistance management programs. Recently, a VGSC haplotype containing two amino acid substitutions associated with resistance in other species, V402L and I1527T, was identified. These two VGSC mutations are found in tight linkage and are mutually exclusive to the classical L995F/S mutations.

RESULTS
We identify the presence of the V402L-I1527 T haplotype in resistant An. coluzzii colonized strains and in field populations from Burkina Faso at frequencies higher than previously reported; in some cases almost reaching fixation. Functional validation of V402L in insecticide resistance using a CRISPR/Cas9 genome modified line showed that it confers reduced mortality after exposure to all tested pyrethroids and DDT, but at lower levels compared to L995F. In contrast however to L995F, no fitness costs were identified for mosquitoes carrying V402L under laboratory conditions.

CONCLUSION
The V402L substitution confers pyrethroid resistance in An. gambiae in the absence of any other VGSC substitution and/or alternative resistance mechanisms. The lower fitness cost associated with this kdr mutation may provide a selective advantage over the classical kdr in some settings and genotyping at this locus should be added in the list of resistant alleles for routine screening.

Item Type:	Article
Additional Information:	This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ps.6731. This research was funded in part, by the Wellcome Trust [215894/Z/19/Z] and [200222/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.'
Subjects:	QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes QX Parasitology > Insects. Other Parasites > QX 515 Anopheles QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control WA Public Health > Preventive Medicine > WA 240 Disinfection. Disinfestation. Pesticides (including diseases caused by) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1002/ps.6731
Depositing User:	Samantha Sheldrake
Date Deposited:	30 Nov 2021 17:29
Last Modified:	06 Apr 2022 14:10
URI:	https://archive.lstmed.ac.uk/id/eprint/19500

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