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

Mersimine F M Kouamo, Sulaiman S Ibrahim, Jack Hearn, Jacob M Riveron, Michael Kusimo, Magellan Tchouakui, Terence Ebai, Williams Tchapga, Murielle J Wondji, Helen Irving, Thaddée Boudjeko, Fabrice F Boyom, Charles S Wondji

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number561
JournalGenes
Volume12
Issue number4
DOIs
Publication statusPrint publication - 13 Apr 2021
Externally publishedYes

Keywords

  • Animals
  • Anopheles/genetics
  • DDT/pharmacology
  • Gene Expression Profiling/methods
  • Glutathione Transferase/genetics
  • Humans
  • Insect Proteins/genetics
  • Insecticide Resistance
  • Malaria/transmission
  • Mosquito Vectors/genetics
  • Multigene Family
  • Permethrin/pharmacology
  • Sequence Analysis, RNA
  • Exome Sequencing/methods
  • GlutathioneS-transferase
  • Anopheles funestus
  • Metabolic resistance
  • RNA interference
  • Malaria

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