DEET Repels Ornery Mosquitoes

COMMENTARY

DEET repels ORNery mosquitoes

John A. Pickett*, Michael A. Birkett, and James G. Logan Department of Biological Chemistry, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, United Kingdom

EET ([N-N]-diethyl-m- toluamide) is widely used A around the world as a repellent for mosquitoes and other bitingD insects. It was originally identified by a structure–activity study using synthetic compounds (1). Recently, a number of new compounds with similar activity [e.g., picaridine (2)] have been identified, but DEET remains the gold standard. Despite a tremendous number 1-octen-3-ol ORN Inhibition of 1-octen-3-ol ORN of studies (3), however, a plausible and evidence-based mechanism for DEET’s action has remained elusive. In a recent B study, Ditzen et al. (4) wrote, ‘‘Here we show that DEET blocks electrophysiological responses to olfactory sensory neurons to attractive odors in Anopheles gambiae and Drosophila melanogaster’’ (Fig. 1A). However, in this issue of PNAS, Syed and Leal (5) present a new mechanism that demonstrates that mos- DEET ORN quitoes detect DEET by means of olfac- tion and that this is the direct cause of C their avoidance behavior (Fig. 1B). Various classes of compounds are termed ‘‘insect repellents.’’ Some, such as pyrethroids (e.g., the recently devel- oped metofluthrin) and DDT, work by insecticidal effect, whereby sublethal toxicity causes the insect either to be ineffective in its attack or to escape from the region of insecticide applica- 1-octen-3-ol ORN No inhibition of 1-octen-3-ol ORN tion. Repellency, however, should relate to a behavioral effect caused by percep- Fig. 1. Depiction of mosquito olfactory receptor neuron (ORN) responses. (A) ORN response to the tion at the peripheral sensory nervous attractant 1-octen-3-ol, and to 1-octen-3-ol plus DEET, introduced into the airflow from a single odor system, causing the insect to not bite cartridge, giving the impression that DEET causes ORN inhibition, as stated by Ditzen et al. (4). (B and C) and to leave the prospective host, with However, according to Syed and Leal (5), a separate DEET ORN is responsible for repellency (B), and, when true behavioral repellency involving 1-octen-3-ol and DEET are introduced into the airflow from two different odor cartridges, no ORN avoidance of the source of the repellent inhibition occurs (C). material, whether placed on the prospective host or near it. Until recently, but usually require frequent application. Seal, J. I. Cook, N. M. Stanczyk, two main classes of behavioral insect In addition, some insects apparently can M.A.B., S. J. Clark, S. A. Gezan, L. J. repellents were known: (i) those, like still detect the host by means of a highly Wadhams, and J.A.P., unpublished DEET and picaridine, that have been data). Nonetheless, the repellent value obtained through testing synthetic com- sensitive and selective olfactory-based host-location capability. More recently, of DEET and other compounds derived pounds for repellency in one of the from structure–activity studies far out- forms discussed above; and (ii) those successful attempts have been made to identify experimental repellents derived weighs other currently available repel- that include a wide range of plant essen- lents, so understanding the mechanism tial oil components, often with strong from species closely related to the host range but not naturally acting as hosts by which DEET acts remains of para- aromas as perceived by humans, that act mount importance. (6, 7). There is also considerable prom- against blood-seeking insects presumably Syed and Leal (5) demonstrate the by suggesting a strong plant ecosystem. ise in repellents active against the ma- existence in some insects of specific ol- For best effect, DEET requires good laria mosquito (An. gambiae), the yellow skin coverage, but even with that, the fever mosquito (Aedes aegypti), and C. insects can remain in an irritating cloud impunctatus that have been identified Author contributions: J.A.P., M.A.B., and J.G.L. wrote the around the protected individual. (This is from odors collected by air entrainment paper. particularly evident with the Scottish of humans who show little or no attrac- The authors declare no conflict of interest. biting midge, Culicoides impunctatus.) tiveness to these insects and from cases See companion article on page 13598. The alternative, plant-derived com- where attractiveness is naturally masked *To whom correspondence should be addressed. E-mail: pounds are highly volatile and can repel by the specific compounds giving rise to [email protected]. the insects from the region of the host this repellency (ref. 8 and J.G.L., N. J. © 2008 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807167105 PNAS ͉ September 9, 2008 ͉ vol. 105 ͉ no. 36 ͉ 13195–13196 Downloaded by guest on September 26, 2021 factory receptor neurons (ORNs) that trations lower by an order of magnitude. Syed and Leal (5) go on to show that respond to DEET. These ORNs, which Thus it would appear that DEET, with when DEET is presented experimentally the authors found to be located on the its relatively low volatility, can remain together with known attractants (e.g., antennae and maxillary palps of the on human skin for some time and re- 1-octen-3-ol, for which there is a sepa- Southern house mosquito, Culex quique- lease slowly, by evaporation, to stimulate rate and specific, although sometimes fasciatus, are associated with short, colocated, ORN) in the same odor car- horn-like sensory organs called ‘‘trichoid tridge, the availability of the attractant sensilla.’’ The ORNs respond in a dose- is physically reduced, which gives the dependent manner to DEET, and this Understanding the impression that the insect odorant re- response is associated with behavioral ceptor is inhibited by DEET. Because this phenomenon was not accounted for avoidance, thereby demonstrating true mechanism by which in the controls used by Ditzen et al. (4), behavioral repellency. It is unlikely that DEET acts remains of their proposed mechanism can be ques- a positive response would have evolved tioned, at least for the time being. How- to this compound. Therefore, it is possi- paramount importance. ever, there are quantitative differences ble that the ORNs responding to DEET between the electrophysiological effects have evolved to respond to naturally shown by Ditzen et al. and the “fixitive” occurring compounds that have repel- effect shown by Syed and Leal, and lent properties conveying ecological ben- the ORNs responding to natural essen- these need to be resolved. Nevertheless, efit. Indeed, Syed and Leal show that tial oil repellent components, to which we now have evidence of specific re- certain plant-derived terpenoids (thu- the DEET receptor (possibly as a conse- sponses by ORNs to DEET and confir- jone, eucalyptol, and linalool) cause quence of the unnatural origin DEET) mation that these responses relate to electrophysiological responses at concen- is an order of magnitude less sensitive. avoidance behavior.

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13196 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807167105 Pickett et al. Downloaded by guest on September 26, 2021