Genome-Wide Transcriptional Analysis and Functional Validation Linked a Cluster of Epsilon Glutathione S-Transferases with Insecticide Resistance in the Major Malaria Vector Anopheles funestus across Africa

Genes

FabriceF. Boyom¹  Jack Hearn²  JacobM. Riveron²  Helen Irving²  MersimineF. M. Kouamo³  Magellan Tchouakui³  Williams Tchapga³  Michael Kusimo³  Terence Ebai³  MurielleJ. Wondji³  CharlesS. Wondji³  SulaimanS. Ibrahim³  Thaddée Boudjeko⁴ 

[1] Department of Biochemistry, Faculty of Science, University of Yaoundé 1, Yaoundé P.O. Box 812, Cameroon;Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L35QA, UK;LSTM Research Unit, Centre for Research in Infectious Diseases (CRID), Yaoundé P.O. Box 13591, Cameroon;Laboratory of Phytoprotection and Plant Valorisation (LPVRV), Biotechnology Centre, University of Yaoundé 1, Yaoundé P.O. Box 812, Cameroon;

关键词: malaria;    Anopheles funestus;    metabolic resistance;    glutathioneS-transferase;    RNA interference;   

DOI  :  10.3390/genes12040561

来源: DOAJ

【 摘 要 】

Resistance is threatening the effectiveness of insecticide-based interventions in use for malaria control. Pinpointing genes associated with resistance is crucial for evidence-based resistance management targeting the major malaria vectors. Here, a combination of RNA-seq based genome-wide transcriptional analysis and RNA-silencing in vivo functional validation were used to identify key insecticide resistance genes associated with DDT and DDT/permethrin cross-resistance across Africa. A cluster of glutathione-S-transferase from epsilon group were found to be overexpressed in resistant populations of Anopheles funestus across Africa including GSTe1 [Cameroon (fold change, FC: 2.54), Ghana (4.20), Malawi (2.51)], GSTe2 [Cameroon (4.47), Ghana (7.52), Malawi (2.13)], GSTe3 [Cameroon (2.49), Uganda (2.60)], GSTe4 in Ghana (3.47), GSTe5 [Ghana (2.94), Malawi (2.26)], GSTe6 [Cameroun (3.0), Ghana (3.11), Malawi (3.07), Uganda (3.78)] and GSTe7 (2.39) in Ghana. Validation of GSTe genes expression profiles by qPCR confirmed that the genes are differentially expressed across Africa with a greater overexpression in DDT-resistant mosquitoes. RNAi-based knock-down analyses supported that five GSTe genes are playing a major role in resistance to pyrethroids (permethrin and deltamethrin) and DDT in An. funestus, with a significant recovery of susceptibility observed when GSTe2, 3, 4, 5 and GSTe6 were silenced. These findings established that GSTe3, 4, 5 and 6 contribute to DDT resistance and should be further characterized to identify their specific genetic variants, to help design DNA-based diagnostic assays, as previously done for the 119F-GSTe2 mutation. This study highlights the role of GSTes in the development of resistance to insecticides in malaria vectors and calls for actions to mitigate this resistance.

【 授权许可】

Unknown