The following study was conducted by Scientists from Liverpool School of Tropical Medicine, Liverpool, United Kingdom. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.
Proceedings of the National Academy of Sciences; 116(51): 25764-25772
Functional Genetic Validation of Key Genes Conferring Insecticide Resistance in the Major African Malaria Vector, Anopheles Gambiae
Significance
Insecticide resistance in Anopheles gambiae mosquitoes can derail malaria control programs, and to overcome it, we need to discover the underlying molecular basis. Here, we characterize 3 genes most often associated with insecticide resistance directly by their overproduction in genetically modified An. gambiae. We show that overexpression of each gene confers resistance to representatives of at least 1 insecticide class, and taken together, the 3 genes provide cross-resistance to all 4 major insecticide classes currently used in public health. These data validate the candidate genes as markers to monitor the spread of resistance in mosquito populations. The modified mosquitoes produced are also valuable tools to prescreen the efficacy of new insecticides against existing resistance mechanisms.
Abstract
Resistance in Anopheles gambiae to members of all 4 major classes (pyrethroids, carbamates, organochlorines, and organophosphates) of public health insecticides limits effective control of malaria transmission in Africa. Increase in expression of detoxifying enzymes has been associated with insecticide resistance, but their direct functional validation in An. gambiae is still lacking. Here, we perform transgenic analysis using the GAL4/UAS system to examine insecticide resistance phenotypes conferred by increased expression of the 3 genes—Cyp6m2, Cyp6p3, and Gste2—most often found up-regulated in resistant An. gambiae. We report evidence in An. gambiae that organophosphate and organochlorine resistance is conferred by overexpression of GSTE2 in a broad tissue profile. Pyrethroid and carbamate resistance is bestowed by similar Cyp6p3 overexpression, and Cyp6m2 confers only pyrethroid resistance when overexpressed in the same tissues. Conversely, such Cyp6m2 overexpression increases susceptibility to the organophosphate malathion, presumably due to conversion to the more toxic metabolite, malaoxon. No resistant phenotypes are conferred when either Cyp6 gene overexpression is restricted to the midgut or oenocytes, indicating that neither tissue is involved in insecticide resistance mediated by the candidate P450s examined. Validation of genes conferring resistance provides markers to guide control strategies, and the observed negative cross-resistance due to Cyp6m2 gives credence to proposed dual-insecticide strategies to overcome pyrethroid resistance. These transgenic An. gambiae-resistant lines are being used to test the “resistance-breaking” efficacy of active compounds early in their development.
Source:
Proceedings of the National Academy of Sciences
URL: https://www.pnas.org/content/116/51/25764
Citation:
Adolfi, A., B. Poulton, et al. (2019). “Functional genetic validation of key genes conferring insecticide resistance in the major African malaria vector, Anopheles gambiae.” Proceedings of the National Academy of Sciences 116(51): 25764-25772.
