The mysterious multi-modal repellency of DEET

DEET is the most effective insect repellent available and has been widely used for more than half a century. Here, I review what is known about the olfactory and contact mechanisms of DEET repellency. For mosquitoes, DEET has at least two molecular targets: Odorant Receptors (ORs) mediate the effect of DEET at a distance, while unknown chemoreceptors mediate repellency upon contact. Additionally, the ionotropic receptor Ir40a has recently been identified as a putative DEET chemosensor in Drosophila. The mechanism of how DEET manipulates these molecular targets to induce insect avoidance in the vapor phase is also contested. Two hypotheses are the most likely: DEET activates an innate olfactory neural circuit leading to avoidance of hosts (smell and avoid hypothesis) or DEET has no behavioral effect on its own, but instead acts cooperatively with host odors to drive repellency (confusant hypothesis). Resolving this mystery will inform the search for a new generation of insect repellents.