Sodium channel activation underlies transfluthrin repellency in Aedes aegypti

Authors: ANDREAZZA, FELIPE - Michigan State University; VALBON, WILSON - Michigan State University; WANG, QIANG - Michigan State University; LIU, FENG - Michigan State University; XU, PENG - Michigan State University; BANDASON, ELIZABETH - Michigan State University; CHEN, MENGLI - Zhejiang University; WU, SHAOYING - Michigan State University; SMITH, LETICIA - Cornell University; SCOTT, JEFFREY - Cornell University; JIANG, YOUYA - Jiangsu Kanion Pharmaceutical Co, Ltd; JIANG, DINGXIN - South China Agricultural Univerisity; Zhang, Aijun; OLIVEIRA, EUGENIO - Michigan State University; DONG, KE - Michigan State University

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/7/2021
Publication Date: 7/8/2021
Citation: Andreazza, F., Valbon, W.R., Wang, Q., Liu, F., Xu, P., Bandason, E., Chen, M., Wu, S., Smith, L.B., Scott, J.G., Jiang, Y., Jiang, D., Zhang, A., Oliveira, E.E., Dong, K. 2021. Sodium channel activation underlies transfluthrin repellency in Aedes aegypti. Proceedings of the National Academy of Sciences (PNAS). https://doi.org/10.1371/journal.pntd.0009546.
DOI: https://doi.org/10.1371/journal.pntd.0009546

Interpretive Summary: Vector-transmitted human diseases, such as dengue fever, represent serious global health problems. Pyrethroids, including transfluthrin, are synthetic natural chemicals widely used as mosquito repellents and insecticides due to their low environmental impact. Pyrethroids target certain sodium channels for their insecticidal action. However, the mechanism of pyrethroid repellency remained unclear and controversial. Insect repellency is traditionally thought to be mediated by olfactory receptors. We made two important discoveries related to transfluthrin in this study: 1) repellency is via activation of sodium channels and 2) activation of sodium channel increases power of odorant receptor-mediated repellents, including DEET. Discovery of sodium channel activation as a major mechanism of pyrethroid repellency has broad significance in the study of insect olfaction. It will help scientists to develop more efficient insect repellents for human protection against blood-feeding arthropods. This information will be important to scientists and industry interested in insect repellents.

Technical Abstract: Volatile pyrethroid insecticides, such as transfluthrin, have received great attention as an insect repellent in recent years for controlling human disease vectors. Although it has been long understood that pyrethroids kill insects by prolonged activation of insect voltage-gated sodium channels, the mechanism of pyrethroid repellency remains poorly understood and controversial. Here, we show that transfluthrin is a potent spatial repellent and its vapor could repel Aedes aegypti in a hand-in-cage assay at concentrations as low as 1 ppm. Contrary to previous reports, transfluthrin does not activate olfactory receptor neurons or affect mosquito's ability to sense host odorants and other repellents. Remarkably, transfluthrin enhanced repellency by DEET and several plant-derived repellents that are known to activate odorant receptors (Ors). The 1S-cis isomer of transfluthrin, which does not activate sodium channels, neither elicited repellency nor enhanced Or-mediated repellency by DEET or several plant-derived repellents. Mutations in the voltage-gated sodium channel gene that reduce the potency of transfluthrin on sodium channels decreased transfluthrin repellency, but did not affect repellency by DEET and other repellents. These results not only establish that sodium channel activation, not activation of olfactory receptors, is the principal mechanism of transfluthrin repellency, but also provide a conceptual framework for use of sodium channel activators, to broadly enhance the repellent efficacy of Or-mediated repellents, including DEET, or for developing innovative dual-target repellent formulations to more effectively repel a variety of human disease vectors.