- Author: Kathy Keatley Garvey
(Editor's Note: This breaking news story (Oct. 27) has three connections to the UC Davis Department of Entomology and Nematology. The research began in the department; faculty member Anthony Cornel provided the mosquitoes for this research; and the father of research team member postdoctoral scholar Young-Moo completed two sabbaticals in the lab of nematologist Harry Kaya, emeritus professor, UC Davis Department of Entomology and Nematology.)
“Mosquitoes are considered the most deadly animals on the planet, but unfortunately, not everyone who needs this repellent can afford to use it, and not all who can afford it can use it due to its undesirable properties,” said Professor Leal of the Department of Molecular and Cellular Biology. One of the undesirable properties is smell.
Leal and his team--project scientist Pingxi Xu, postdoctoral scholar Young-Moo Choo, and agricultural and environmental chemistry graduate student Alyssa De La Rosa--published their groundbreaking research, “Mosquito Odorant Receptor for DEET and Methyl Jasmonate,” today (Oct. 27) in the Proceedings of the National Academy of Sciences (PNAS).
They examined the receptors of the southern house mosquito, Culex quinquefasciatus, which transmits such diseases as West Nile virus. Mosquitoes detect DEET and other smells with their antennae.
They discovered that the direct activation of an odorant receptor, not an ionotrophic receptor, “is necessary for DEET reception and repellency in Culex mosquitoes.” They also detected a link between DEET and methyl jasmonate, thus suggesting that DEET might work by mimicking a defensive compound from plants.
“Vector-borne diseases are major health problems for travelers and populations living in endemic regions,” said Leal. “Among the most notorious vectors are mosquitoes that unwittingly transmit the protozoan parasites causing malaria and viruses that cause infections, such as dengue, yellow fever, chikungunya, and encephalitis.”
Leal said that diseases transmitted by mosquitoes destroy more lives annually “than war, terrorism, gun violence, and other human maladies combined. Every year, malaria decimates countless lives – imagine a city of San Francisco perishing to malaria year after year. The suffering and economic consequences in endemic areas are beyond imagination for those living in malaria-free countries. Both natives and visitors to endemic areas want to keep these ‘infected needles' at bay. In the absence of vaccines for malaria, dengue, and encephalitis, one of the most ancient and effective prophylactic measures against mosquito-borne diseases is the use of DEET.”
Dan Strickman of the Bill and Melinda Gates Foundation, not involved in the study, praised the work. “We are at a very exciting time for research on insect repellents,” said Strickman, senior program officer of the Global Health Program's Vector Control. “ For decades, the field concentrated on screening compounds for activity, with little or no understanding of how chemicals interacted with mosquitoes to discourage biting. Use of modern techniques that combine molecular biology, biochemistry, and physiology has generated evidence on how mosquitoes perceive odors.”
Strickman said the paper makes “a convincing case” that the principal repellent active ingredients activate a particular odorant receptor in mosquitoes.
The same receptor, Strickman noted, is activated by a naturally occurring plant defensive compound, “suggesting that synthetic repellents take advantage of the same mechanisms that plants have developed as a result of selection exerted by herbivorous insects.”
Strickman called the research “a fascinating biological story, but it also opens the door to systematic development of highly effective repellents that would create a big improvement in personal protection. In theory, a compound that was 100,000 times more effective than current repellents might be used at much lower concentration and create completely new ways to prevent mosquito bites.”
Said zoologist Paul Weldon of the Smithsonian's Conservation Biologist Institute, also not involved in the study: “Since DEET is strictly synthetic and not a natural product, it has been challenging to understand the adaptive nature of the response it elicits. It is not as if the compound emanates from, say, spider webs or fishy water, where avoidance by mosquitoes would make sense. Xu et al. have solved the mystery of where the DEET response comes from: it is in response to plant chemical defenses.”
“This, by the way, also explains why the DEET response is widespread, occurring in many arthropods, including those that are not ectoparasitic -- like cockroaches,” Weldon said. The repellence of other arthropods by DEET may have tipped off some of those investigating the DEET response, but I'm not sure that it did. The focus of research on DEET seems to have been with the organisms in which it just so happened to be discovered -- mosquitoes. The Xu et al. study suggests that there is a much broader array of DEET-sensitive organisms than previously suspected. No doubt, this finding will assist further investigations of it.”
Professor John Pickett, Rothamsted Research, UK, also not involved in the study, called the link between the plant compound and synthetic insect repellent, DEET as a “surprising evolutionary link.”
Pickett, the Michael Elliott Distinguished Research Fellow and Scientific Leader of Chemical Ecology at Rothamsted Research and a foreign associate of the National Academy of Sciences, said: “Not only does this work demonstrate that a mosquito response to the gold standard repellent DEET, as well as the more recently developed repellents, is mediated by a specific odorant receptor (OR136 for the southern house mosquito Culex quinquefasciatus) but that the receptor responds specifically also to methyl jasmonate, involved in plant hormone-based defense against insects, which suggests a surprising evolutionary link between these types of insect interactions.”
The UC Davis researchers pointed out that “insect repellents have been used since ancient times as prophylactic agents against diseases transmitted by mosquitoes and other arthropods, including malaria, dengue fever, and encephalitis. They were developed from plant-based smoke or extracts (essential oils) into formulations with a single active ingredient.”
Progress toward development of better and more affordable repellents has been slow, they said, because scientists weren't sure which odorant receptor was involved.
Mosquito researcher Anthony Cornel, associate professor with the UC Davis Department of Entomology and Nematology, and based at the Kearney Agricultural Research and Extension Center, Parlier, provided mosquitoes that allowed the Leal lab to duplicate his mosquito colony at UC Davis. Richard Benton of the University of Lausanne, Switzerland shared his flies, Drosophila plasmids, also part of the research. (See related story on Anthony Cornel)
The work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
The Leal lab published groundbreaking research in 2008 in PNAS that found that mosquitoes avoid DEET because mosquitoes dislike the smell, not because it masks the smell of the host or jams the senses. “Mosquitoes don't like it because it smells bad to them,” Leal said at the time.
More than 200 million people worldwide use the chemical insect repellent, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946.
Related Links:
Procedings of the National Academy of Sciences (PDF)
Anthony Cornel: Mosquito Man
Close Connections (Like Father, Like Son)
News Media Contacts:
Walter Leal
Professor, Department of Molecular and Cellular Biology
Email: wsleal@ucdavis.edu
Phone: 530-752-7755
Website: http://chemecol.ucdavis.edu\
Pat Bailey
Science/agricultural writer
UC Davis News and Media Relations
Office Phone: (530) 752-9843
Cell phone: (530) 219-9640
Email: Pjbailey@ucdavis.edu
- Author: Kathy Keatley Garvey
See published paper in PNAS (Embargoed lifted at 2 p.m. Pacific Standard Time, Aug. 18, 2008)
Link to video from Walter Leal lab
Listen to BBC interview of Walter Leal from Web site or link directly to: MP3 or WAV.
“We found that mosquitoes can smell DEET and they stay away from it,” said noted chemical ecologist Walter Leal, professor of entomology at UC Davis. “DEET doesn't mask the smell of the host or jam the insect's senses. Mosquitoes don't like it because it smells bad to them.”
DEET's mode of action or how it works has puzzled scientists for more than 50 years. The chemical insect repellent, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946, is considered the “gold standard” of insect repellants worldwide. Worldwide, more than 200 million use DEET to ward off vectorborne diseases.
Scientists long surmised that DEET masks the smell of the host, or jams or corrupts the insect's senses, interfering with its ability to locate a host. Mosquitoes and other blood-feeding insects find their hosts by body heat, skin odors, carbon dioxide (breath), or visual stimuli. Females need a blood meal to develop their eggs.
Said Miller: "For decades we were told that DEET warded off mosquito bites because it blocked insect response to lactic acid from the host -- the key stimulus for blood-feeding. Dr. Leal and co-workers escaped the key stimulus over-simplification to show that mosquito responses -- like our own -- result from a balancing of various positive and negative factors, all impinging on a tiny brain more capable than most people think of sophisticated decision-making.”
“This new work corrects long-standing erroneous dogma, and shows that recent work on DEET mode-of-action published in the flagship journal, Science, apparently was flat-out wrong,” Miller said. “One of the great attributes of science is that, over time, it is self-correcting."
Leal said previous findings of other scientists showed a “false positive” resulting from the experimental design.
The UC Davis work, “Mosquitoes Smell and Avoid the Insect Repellent DEET,” is published in the Aug. 18 edition of the Proceedings of the National Academy of Sciences (PNAS).
Mosquitoes detect DEET and other smells with their antennae. Leal and researcher Zain Syed discovered the exact neurons on the antennae that detect DEET (N,N-diethyl-3-methylbenzamide). These neurons are located beside other neurons that sense a chemical, 1-octen-3-ol, known to attract mosquitoes.
The UC Davis investigators set up odorless sugar-feeding stations, some containing DEET, and found that DEET actively repelled them. The mosquitoes they used were Culex quinquefasciatus, also known as the Southern house mosquito. The mosquito transmits West Nile virus, St. Louis encephalitis, and lymphatic filariasis, a disease caused by threadlike parasitic worms.
“Despite the fact DEET is the industry standard mosquito repellent, relatively little is known about how it actually works,” said UC Davis research entomologist William Reisen. “Previous studies have suggested a 'masking' or 'binding' with host emanations. Understanding the mode of action is especially important because DEET is used as the standard against which all other tentative replacement repellents are compared.
Reisen said that Leal and Syed “have performed an exhausting series of sophisticated, directed, yet straight-forward experiments to determine that the mode of action of DEET is mostly due to the response of a specific sensilla to DEET. Although there may be some host odor 'binding,' the critical finding that DEET inhibited sugar feeding clearly showed that mosquitoes of both sexes detected DEET and were repelled, even without a host being present.”
Said Major Dhillon, president of the American Mosquito Control Association and district manager of the Northwest Mosquito and Vector Control District, Riverside: “It certainly is a breakthrough. In the future, this new knowledge can be incorporated into developing new repellents and may be in control strategies for Culex quinquefasciatus and other mosquitoes.”
Research chemist Uli Bernier of the Mosquito and Fly Research Unit, USDA Agricultural Research Service, described the UC Davis study as “an excellent explanation.” Bernier, who studies how repellents impact mosquitoes' feeding behavior, said the Leal-Syed work “presents as a very logical basis to help us understand how DEET is perceived by the mosquitoes, and this work provides an excellent explanation to link physiological processing within the mosquito to the (macroscopic) behavioral response that we observe in laboratory bioassays with this repellent."
Leal, a past president of the International Society of Chemical Ecology, received the 2007 Silverstein-Simeone Lecture Award for his innovative research on how insects detect smells and communicate within their species. He is a former chair of the UC Davis Department of Entomology.
Resources:
Download high-resolution photo, Culex quinquefasciatus (Kathy Keatley Garvey, UC Davis Department of Entomology)
Download high-resolution photo of Culex quinquefasciatus on arm (Kathy Keatley Garvey, UC Davis Department of Entomology)
Download high-resolution spray photo http://169.237.77.3/news/images/culexquinquefasciatuspnas.jpg(Kathy Keatley Garvey, UC Davis Department of Entomology)
PNAS paper (PDF)
Science article (March 2008) referred to by James Miller