title: Pyrethroid Resistance in Malaysian Populations of Dengue Vector Aedes aegypti Is Mediated by CYP9 Family of Cytochrome P450 Genes.
abstract: Dengue control and prevention rely heavily on insecticide-based interventions. However, insecticide resistance in the dengue vector Aedes aegypti, threatens the continued effectiveness of these tools. The molecular basis of the resistance remains uncharacterised in many endemic countries including Malaysia, preventing the design of evidence-based resistance management. Here, we investigated the underlying molecular basis of multiple insecticide resistance in Ae. aegypti populations across Malaysia detecting the major genes driving the metabolic resistance.
  
  
  
  Genome-wide microarray-based transcription analysis was carried out to detect the genes associated with metabolic resistance in these populations. Comparisons of the susceptible New Orleans strain to three non-exposed multiple insecticide resistant field strains; Penang, Kuala Lumpur and Kota Bharu detected 2605, 1480 and 425 differentially expressed transcripts respectively (fold-change>2 and p-value ≤ 0.05). 204 genes were commonly over-expressed with monooxygenase P450 genes (CYP9J27, CYP6CB1, CYP9J26 and CYP9M4) consistently the most up-regulated detoxification genes in all populations, indicating that they possibly play an important role in the resistance. In addition, glutathione S-transferases, carboxylesterases and other gene families commonly associated with insecticide resistance were also over-expressed. Gene Ontology (GO) enrichment analysis indicated an over-representation of GO terms linked to resistance such as monooxygenases, carboxylesterases, glutathione S-transferases and heme-binding. Polymorphism analysis of CYP9J27 sequences revealed a high level of polymorphism (except in Joho Bharu), suggesting a limited directional selection on this gene. In silico analysis of CYP9J27 activity through modelling and docking simulations suggested that this gene is involved in the multiple resistance in Malaysian populations as it is predicted to metabolise pyrethroids, DDT and bendiocarb.
  
  
  
  The predominant over-expression of cytochrome P450s suggests that synergist-based (PBO) control tools could be utilised to improve control of this major dengue vector across Malaysia.
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.|School of Biological Sciences, Universiti Sains Malaysia, Penang, Malaysia.
authors.forename: Intan H
authors.initials: IH
authors.lastname: Ishak
authors.affiliation: Research Unit of Liverpool School of Tropical Medicine at Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, Yaoundé, Cameroon.
authors.forename: Basile
authors.initials: B
authors.lastname: Kamgang
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.|Department of Biochemistry, Bayero University, PMB, Kano, Nigeria.
authors.forename: Sulaiman S
authors.initials: SS
authors.lastname: Ibrahim
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.|Research Unit of Liverpool School of Tropical Medicine at Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, Yaoundé, Cameroon.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Riveron
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Irving
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom.|Research Unit of Liverpool School of Tropical Medicine at Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, Yaoundé, Cameroon.
authors.forename: Charles S
authors.identifier: 0000-0003-0791-3673
authors.initials: CS
authors.lastname: Wondji
mesh_terms: D000330:Aedes / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003715:Dengue / Q000635:transmission; D005260:Female; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D007303:Insect Vectors / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D007305:Insecticide Resistance; D007306:Insecticides / Q000494:pharmacology*; D008296:Malaysia; D011110:Polymorphism, Genetic; D011722:Pyrethrins / Q000494:pharmacology*
chemical_list: D019476:Insect Proteins; D007306:Insecticides; D011722:Pyrethrins; D003577:Cytochrome P-450 Enzyme System