Distracting the hungry: mosquito anosmia‐inducing and odor perception‐enhancing compounds of natural origin targeting ORco function for control of transmission of malaria and other mosquito‐borne infectious diseases

Abstract

ORco, the ubiquitous co‐receptor of insect olfactory receptors, is an essential constituent of the insect olfactory machinery. Mutations affecting ORco function and RNAi‐mediated reduction in ORco abundance impact negatively on the organisms' capacity to detect the normal odor repertoire. On the other hand, compounds acting as ORco agonists may impact in a positive fashion on the function of olfactory receptors. In the current study, we have employed lepidopteran (Bombyx mori and Trichoplusia ni) cell‐based screening platforms expressing ORco and olfactory receptor variable subunits (ORx) of Anopheles gambiae in conjunction with specific ligand‐dependent functional assays to assess the effects of specific constituents of essential oils on receptor functionality. We show that natural compounds, previously selected through screening work employing A. gambiae odorant binding proteins (OBPs) with female expression bias, and displaying spatial repellent properties against Anopheles and Culex mosquitoes similar to or stronger than those of DEET, are, in fact, ORco antagonists. These antagonists cause chemical ablation of the function of all tested heteromeric olfactory receptor complexes containing ORco, and may induce anosmia‐like disorientation effects on mosquitoes. On the other hand, we show that members of a known class of synthetic ORco agonists induce allosteric changes on receptor heteromers resulting in significant ORx ligand‐specific enhancement in odor perception in vitro. Because these ORco agonists are not volatile and thus cannot be detected by mosquitoes at a distance, we are using the odorant receptor expression platforms to screen essential oils obtained from Mediterranean aromatic plants for the presence of natural volatiles acting as specific ORco agonists with functional properties similar to those of the synthetic agonists. In parallel, we are expanding the screens for the isolation of additional natural ORco antagonists. Due to their volatile nature, the natural anosmia‐inducing compounds would be expected to act at a distance and thus be suitable for use as spatial disorienting agents. The same principle should be applicable to the natural olfactory enhancers, which may be used as additives to human odor blend‐containing mosquito traps for more effective trapping. The combined deployment of anosmia‐inducing and olfactory capacity‐enhancing compounds targeting ORco function may provide a most effective approach for protection against indoor and outdoor transmission of malaria and other mosquito‐borne infectious diseases.Support or Funding InformationThis work has been supported by the ENAROMaTIC consortium project (grant No FP7‐222927 of the EC) and was carried out in facilities of the OPENSCREEN‐GR National (Greece) Research Infrastructure.