Project Summary/Abstract Mosquitoes are vectors of pathogens and arboviruses, including malaria, dengue, chikungunya, West Nile virus, and the Zika virus. With the growing concerns regarding insecticide spraying into the environment and given the increasing cases of mosquitoes’ resistance to pesticides, environmentally friendly strategies for monitoring, surveillance, and controlling populations of mosquitoes are sorely needed. One such strategy is the use of oviposition attractants as lures for surveillance, monitoring, and potentially controlling mosquito populations when combined with a toxic agent. This project is aimed at advancing our understanding of the molecular basis of mosquito olfaction, specifically, how inhibitory compounds may interfere with the reception of oviposition attractants and other odorants, and at using odorant receptors to guide isolation and identification of oviposition attractants from natural sources. The proposed research will strengthen existing collaboration among vector biologists addressing fundamental questions in olfaction and those with hands-on experience, including colleagues involved in controlling populations of the southern house mosquito and the invasive yellow fever mosquito in areas where the Zika virus is currently causing or threatens to cause an infectious epidemic. In Aim #1, we will investigate both whether agonists and inhibitory compounds act on different binding sites of “inhibitory” odorant receptors (ORs) and the mechanism(s) of receptor inhibition. Aim #2 will address whether ORs, including “inhibitory” ORs, are co-expressed in antennal neurons, and whether these “inhibitory” receptors affect the behavior of neurons, particularly those responding to oviposition attractants. In Aim #3, we will search the genomes of the yellow fever mosquito and the southern house mosquito for orthologs and other “inhibitory” receptors. In Aim #4, we will use odorant receptors, particularly those sensitive to oviposition attractants, to prospect for novel attracts from natural sources, including essential oils and extracts from conspecific larvae. OR-guided isolation of active ingredients will be followed by chemical characterization and synthesis. The new lures will be tested first in indoor behavioral assays and subsequently in the fields in Clovis, California and in Recife, Brazil, the epicenter of the Zika epidemic.