Insects such as mosquitoes use their olfactory and gustatory systems to find their hosts and in the process can transmit deadly diseases to hundreds of millions of people worldwide causing substantial mortality and morbidity. The chemosensory receptors therefore provide excellent targets to design behavior disruption strategies. The insect repellent DEET is effective against a variety of insects including mosquitoes; however it is rarely used by the population at risk in tropical countries due to high costs relative to incomes, and the inconvenience of continuous application on skin. The effectiveness of DEET is due in part to it being detected by aversive receptors in both the olfactory and the gustatory system; however nothing was known about their identity. In a recent breakthrough using the model system Drosophila melanogaster we have identified a DEET-detecting neuron in the antenna that expresses Ir40a and we have shown that both the neuron and the gene are required for avoidance. We have also developed a cheminformatic method to predict new ligands for the DEET receptor that are from natural sources including compounds found in food and flavoring. The goal of this proposal is to identify the conserved DEET-sensing olfactory and gustatory receptors and utilize them as targets to create novel classes of powerful broad-spectrum insect repellents that are safe and affordable. In addition high-throughput assay platforms with the target receptors for DEET will be created, which will serve as a foundation for discovery of even better repellents in the future. For this proposal we plan to use an array of technologies that involve chemical-informatics, neurophysiology, and behavioral analysis. First, we plan to validate the role of the Ir40a/Ir93a/Ir25a in detection of DEET and use them to test the computationally predicted ligands. Second, we plan to identify gustatory receptors that detect DEET as bitter and then test the predicted ligands as bitter aversive compounds. Third, we propose to identify neuronal circuits in the higher brain centers that process the aversive behavior from the olfactory and gustatory system. And fourth, we will test the dual aversive compounds for repellency in Aedes aegypti mosquitoes transmits Dengue and Yellow fever. Successful completion of this proposal will provide safe, affordable and pleasant smelling odorants that are better than DEET in reducing contact between humans and mosquitoes.

Public Health Relevance

Mosquitoes such as Aedes aegypti transmit the Dengue virus and Yellow fever virus to millions of people every year. Diseases such as Dengue are anticipated to remain a major health problem globally due to a lack of vaccines, and lack of effective control methods for the vector. Behavioral repellents that inhibit mosquito-human contact can play an important role in controlling the spread of diseases if they were effective, affordable and convenient for widespread use. Successful completion of this proposal will lead to identification of a new generation of broad-spectrum insect repellents that can block host-seeking mosquitoes and other insects from human contact.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Sullivan, Susan L
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University of California Riverside
Earth Sciences/Resources
United States
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MacWilliam, Dyan; Kowalewski, Joel; Kumar, Arun et al. (2018) Signaling Mode of the Broad-Spectrum Conserved CO2 Receptor Is One of the Important Determinants of Odor Valence in Drosophila. Neuron 97:1153-1167.e4
Chen, Yu-Chieh David; Dahanukar, Anupama (2017) Molecular and Cellular Organization of Taste Neurons in Adult Drosophila Pharynx. Cell Rep 21:2978-2991
Clark, Jonathan T; Ray, Anandasankar (2016) Olfactory Mechanisms for Discovery of Odorants to Reduce Insect-Host Contact. J Chem Ecol 42:919-930
Krause Pham, Christine; Ray, Anandasankar (2015) Conservation of Olfactory Avoidance in Drosophila Species and Identification of Repellents for Drosophila suzukii. Sci Rep 5:11527
Ray, Anandasankar (2015) Reception of odors and repellents in mosquitoes. Curr Opin Neurobiol 34:158-64