Allelic variation in a cluster of epsilon glutathione S-transferase genes contributes to DDT and pyrethroid resistance in the major African malaria vector Anopheles funestus

Kouamo, Mersimine F. M., Ibrahim, Sulaiman S., Muhammad, Abdullahi, Gadji, Mahamat, Hearn, Jack and Wondji, Charles ORCID: https://orcid.org/0000-0003-0791-3673 (2025) 'Allelic variation in a cluster of epsilon glutathione S-transferase genes contributes to DDT and pyrethroid resistance in the major African malaria vector Anopheles funestus'. BMC Genomics, Vol 26, Issue 1, p. 452.

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Abstract

Background
Insecticide resistance in malaria vectors is a serious challenge to malaria control and elimination. Elucidation of the role of detoxification genes in resistance is necessary to develop targeted strategies to reduce malaria burden. Glutathione S-transferase epsilon clusters (GSTe genes) are upregulated in DDT- and pyrethroid-resistant Anopheles funestus mosquitoes across Africa. However, except for GSTe2, the molecular mechanisms behind this upregulation remain unclear. Here, we established that overexpression and allelic variation of GSTe genes contribute to insecticide resistance in African malaria vector An. funestus s.s.

Methods
Transcriptomic and genomic analyses of GSTe genes were conducted, followed by in silico structural analysis, and functional characterization of GSTe3, GSTe4 and GSTe6 using metabolic assay and transgenic expression in Drosophila flies.

Results
Transcriptomic and genomic analyses reveal changes in gene expression and genetic diversity of GSTes cluster in An. funestus across Africa. Cloning of cDNAs of GSTes from different regions of Africa detected allelic variants under selection, including A17D26T158-GSTe3, L135H191A189-GSTe4 in West/Central Africa, and T169S201 E210-GSTe6 present only in West/Southern Africa. Furthermore, in silico analysis of BN-GSTe3, MWI-GSTe3, BN-GSTe4, MWI-GSTe4, CMR-GSTe6 and, BN-GSTe6 alleles revealed that allelic variations increase the binding cavity in the active site of these GSTes with stronger affinities observed towards DDT and permethrin. All recombinant GSTes significantly metabolize DDT (41–63%) and permethrin (13–25%). Additionally, BN-GSTe4 (L135H191A189-GSTe4) variant significantly metabolizes deltamethrin (28.75%), compared to the wild-type allele (15.99%; p < 0.05). Transgenic expression of the GSTes in Drosophila melanogaster flies revealed reduced DDT mortalities in flies expressing the selected alleles (39–55%; p˂0.001), compared to control group (98%). Similar resistance patterns were observed toward permethrin and deltamethrin.

Conclusion
These findings established the role of GSTes in conferring cross-resistance to pyrethroids and DDT, highlighting the role of these genes in metabolic resistance in An. funestus, which complicates malaria control using the above key insecticides.

Item Type:	Article
Subjects:	QX Parasitology > Insects. Other Parasites > QX 650 Insect vectors WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1186/s12864-025-11637-3
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	28 May 2025 10:05
Last Modified:	28 May 2025 10:05
URI:	https://archive.lstmed.ac.uk/id/eprint/26683

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