Mosquitoes with null mutations in the orco olfactory co-receptor have reduced preference for humans, are only attracted to human odour in the presence of CO2 and are not repelled by the odour of the insect repellent DEET. The most dangerous vectors of human disease, such as Anopheles gambiae and Aedes aegypti, differ from less-threating types by having a strong preference for human blood as opposed to a broader diet of vertebrate blood. How mosquitoes distinguish humans from non-humans is not understood. Here Leslie Vosshall and colleagues have developed gene-targeting in A. aegypti mosquitoes to produce mutant females that retain a strong attraction to both human and animal hosts in the presence of carbon dioxide (the exhaled gas acts as an attractant) but no longer prefer humans. The mutation disrupts the orco gene, which codes for a co-receptor that is essential for all insect odorant receptors. Interestingly the orco-mutant female mosquitoes were attracted to humans even in the presence of the insect repellant DEET, although they were repelled upon contact. This indicates that there are both olfactory- and contact-mediated effects of DEET. Female mosquitoes of some species are generalists and will blood-feed on a variety of vertebrate hosts, whereas others display marked host preference. Anopheles gambiae and Aedes aegypti have evolved a strong preference for humans, making them dangerously efficient vectors of malaria and Dengue haemorrhagic fever1. Specific host odours probably drive this strong preference because other attractive cues, including body heat and exhaled carbon dioxide (CO2), are common to all warm-blooded hosts2,3. Insects sense odours via several chemosensory receptor families, including the odorant receptors (ORs), membrane proteins that form heteromeric odour-gated ion channels4,5 comprising a variable ligand-selective subunit and an obligate co-receptor called Orco (ref. 6). Here we use zinc-finger nucleases to generate targeted mutations in the orco gene of A. aegypti to examine the contribution of Orco and the odorant receptor pathway to mosquito host selection and sensitivity to the insect repellent DEET (N,N-diethyl-meta-toluamide). orco mutant olfactory sensory neurons have greatly reduced spontaneous activity and lack odour-evoked responses. Behaviourally, orco mutant mosquitoes have severely reduced attraction to honey, an odour cue related to floral nectar, and do not respond to human scent in the absence of CO2. However, in the presence of CO2, female orco mutant mosquitoes retain strong attraction to both human and animal hosts, but no longer strongly prefer humans. orco mutant females are attracted to human hosts even in the presence of DEET, but are repelled upon contact, indicating that olfactory- and contact-mediated effects of DEET are mechanistically distinct. We conclude that the odorant receptor pathway is crucial for an anthropophilic vector mosquito to discriminate human from non-human hosts and to be effectively repelled by volatile DEET.

orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET