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European Network for Advanced Research on Olfaction for Malaria Transmitting Insect Control

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Disrupting human odour detection in mosquitoes

Malaria, spread by female anopheline mosquitoes, causes about one million deaths every year. Treatment approaches such as insecticides and insecticide-treated bed nets have been ineffective besides being toxic and ecologically unfriendly.

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The multinational, multidisciplinary 'European network for advanced research on olfaction for malaria transmitting insect control' (ENAROMATIC) project funded by the EU has developed control products to prevent the spread of malaria by disrupting human odour sensing in insects. Natural and synthetic compounds that act on odorant-binding proteins (OBPs) and odorant receptors (ORs) in mosquitoes were isolated using modelling and rational design. Several milestones were achieved during the project. Twelve OBPs and 11 ORs predominantly found in female olfactory sensilla were cloned and expressed in bacteria and lepidopteran insect cells. Insect cell-based high-throughput screening (HTS) assays proved particularly useful in rapidly screening compounds for OR-specific ligands and elucidating ligand-dependent olfactory receptor function and behaviour modifiers. These assays are robust, information-rich, user friendly and reliable for pharmacological characterisation of mosquito receptors as well as testing ligand-matched OBP–OR pairs. Whole mount fluorescence in situ hybridisation (WM-FISH), confocal laser scanning microscopy and immuno-histochemistry helped elucidate the distribution of OBPs and ORs in mosquito antenna sensilla. High titre antisera, mRNAs and OR/OBP-specific riboprobes were generated. Immunolocalisation studies demonstrated the role of OBP–OR pairs in odour detection based on sensillum type. Gas chromatography-coupled electroantennograms (GC-EAGs) combined with a warm body repellent assay for Anopheles gambiae females was used to test 82 extracts from various aromatic plants. Twenty-one tested oils (extracts) demonstrated strong reduction in mosquito landings on a warm body. Five strongly repellent extracts were structurally analysed using GC mass spectrometry to understand behaviour-modifying constituents and derivatives. X-ray crystallography of 10 promising OBPs demonstrated variation in binding cavities and other properties that are responsible for differences in OBPs and their binding specificity. Computational models were also built to study protein–ligand interactions in OBPs of interest; results were validated using site-specific mutagenesis. The studies should optimise compounds for effective alteration of human odour detection. Mammalian neuronal network microelectrode array (MEA) neurochips assessed the cytotoxicity and neurotoxicity of the selected repellent compounds in comparison to widely used DEET and EBAAP. Tests revealed no toxicity at intended dosages for external application with adverse effects only in the case of ingestion. Model huts and field conditions in Nigeria were used to test female mosquito (anophelines and culicines) behaviour on exposure to odour-disrupting repellent compounds. Researchers avoided human or animal contact with mosquitoes by using mosquito traps. The setup proved ideal for studying mosquito behaviour and testing new control tools. ENAROMATIC researchers have successfully demonstrated the feasibility of olfaction-based modification of mosquito behaviour in reducing malaria transmission.

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