- 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.
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- Author: Kathy Keatley Garvey
The yellow fever mosquito, Aedes aegypti, a newly invasive species in central California? Check.
The West Nile virus mosquito, Culex quinquefasciatus, found throughout much of the world? Check.
The malaria mosquito, Anopheles gambiae, which wreaks worldwide havoc? Check.
Cornel's name appeared in the news this week when the UC Davis lab of Walter Leal announced that it had found the odorant receptor that repels DEET in the southern house mosquito, Culex quinquefasciatus mosquito. Cornel provided the mosquitoes that allowed the Leal lab to duplicate his colony. Proceedings of the National Academy of Sciences (PNAS) published the work Oct. 27.
Cornel's main research keys in on the population genetics and ecology of West Nile virus vectors in the United States and population genetics and ecology of major malaria vectors in Africa.
“Anton is a great asset to our program, a wonderful colleague, and a nice team player,” said Leal, a professor in the Department of Molecular and Cellular Biology. “We benefit greatly from his generosity by sharing not only mosquito colonies, but also his encyclopedic knowledge on mosquito biology and ecology. We shared co-authorship in a number of publications, and many more are coming.”
Cornel collaborates with Leal on oviposition attraction in Culex quinquefasciatus and “we are now endeavoring to come up with effective oviposition attractive chemical lures to use in virus surveillance and kill traps.”
“The invasion of Aedes aegypti into central California has been of great concern especially as current control methods do not appear to be working very well,” said Cornel, who works closely with state's mosquito abatement personnel. “We have found that the Aedes aegypti have insecticide resistance genes which likely explains why their ultra-low volume (ULV) and barrier spray applications have not worked as well as expected. Work will be ongoing next year when the Aedes aegypti become active again after a brief slow overwintering period from November to March.”
A native of South Africa, Cornel received his doctorate in entomology, focusing on mosquito systematics, in 1993 from the University of the Witwatersrand, Johannesburg. He completed a post-doctoral fellowship with the Entomology Branch of the Centers for Disease Control and Prevention, Atlanta, before joining UC Davis in 1997 as an assistant professor and researcher.
“Who would have thought that that the expertise that I gained on West Nile virus as a master student in South Africa would be used many years later after West Nile virus invaded and spread throughout the USA?”
For more than two decades, Cornel has teamed with fellow medical entomologist and “blood brother” Professor Gregory Lanzaro of the UC Davis School of Veterinary Medicine to study malaria mosquitoes in the West African country of Mali. Their work is starting to show significant results.
“Because of our commitment to conduct long term longitudinal studies and not static investigations,” Cornel said, “we have now shown that considerable selective processes are taking place causing spatiotemporal dynamics of gene flow and fitness events in major malaria vectors M (now Anopheles coluzzii) and S (now Anopheles gambiae) and M/S hybrids in West Africa.” Their work was published in PNAS in 2013 (vol:110:49).
“We are currently establishing further evidence of the important role of insecticide resistance traits in spatiotemporal dynamics of Anopheles coluzzii, Anopheles gambiae and the Bamako form.” Cornel noted that these results have “considerably important implications in future efficacies of insecticide treated bednets to control indoor biting malaria vectors in West Africa.”
Cornel also teams with Lanzaro and Professor Heather Ferguson of the University of Glasgow to examine the ecology and associated genetics of the major malaria vector Anopheles arabiensis in Tanzania. They began working on the project four years ago.
“We are looking at the effects of bednet use and changes in feeding patterns of this mosquito taking population structure into consideration,” Cornel said. He and his colleagues published a paper in November 2013 in G3: Genes, Genome and Genetics, titled “Diversity, Differentiation, and Linkage Disequilibrium: Prospects for Association Mapping in the Malaria Vector Anopheles arabiensis."
One of his newest projects is the study of population/genetics, insecticide resistance and cytogenetics in the major malaria vector in Brazil. Cornel and Lanzaro launched their study in September when they traveled to Brazil to begin targeting the culprit, Anopheles darlingi, a “widely distributed species that has adapted to survive in multiple ecological zones and we suspect that it may consist of multiple incipient or closely related species,” Cornel said.
“While in Brazil I collected larvae and dissected salivary glands from them to examine their polytene chromosome inversion structure and polymorphisms,” Cornel related. “Inversions are vitally important to consider in genetic analyses and it takes considerable patience to interpret the chromosomes.”
Cornel and Lanzaro collaborate with Professor Paulo Pimenta of the Laboratory of Medical Entomology, René Rachou Research Centre- FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil. The UC Davis medical entomologists hope to produce good preliminary data from their research trip to write grants and establish a long-term project in Brazil.
Cornel also studies avian malaria. That interest sparked four years ago when he began working in Cameroon with scientists from UCLA and San Francisco State University (SFSU), including SFSU's Ravinger Sehgal, who studies avian blood parasites. Cornel's graduate student Jenny Carlson, in her final year of her Ph.D studies, is investigating avian malaria in Fresno County.
The Cornel-Carlson research implicates that considerable fidelity exists between Culex mosquito species and species of plasmodium they transmit. “This is contrary to the currently held belief that all Culex mosquitoes are equally capable of transmitting avian malaria,” Cornel said. “In our investigations, we described a new species of avian malaria which is very common in songbirds in Fresno County (published in Parasitology Research).”
Cornel plans to continue working with Sehgal investigating the effects of deforestation on transmission of avian parasites in Cameroon. They recently submitted a National Science Foundation grant proposal. “A large swath of primary forest is slated to be deforested in Cameroon and replaced with Palm oil plantations and we will investigate the effects of this hopefully, as it happens.”
Cornel will be starting a new mosquito-borne virus project in February. He received a Carnegie Foundation scholarly three-month fellowship to work in South Africa (February through to April). The primary objective of the project? To examine mosquito-borne viruses cycling in seven national parks in South Africa and two National Parks in Bostwana.
“It's extremely difficult to get permission to conduct field research in national parks in Southern Africa and this provides an unprecedented exciting opportunity for me to work with a friend, Professor Leo Braack from the University of Pretoria, in these parks. One has to be very careful working in some of these parks at night because of the wild predators, elephants, hippos and buffalo.”
Cornel is active in the 30- member Center for Vectorborne Diseases (CVEC), headquartered in the UC Davis School of Veterinary Medicine and considered the most comprehensive vectorborne disease program in California. Both interdisciplinary and global, CVEC encompasses biological, medical, veterinary and social sciences. Globally, the major emphasis is on research and education involving diseases such as malaria, dengue and leishmaniasis in the developing world. CVEC members study molecular biology, virology, parasitology, vector control, and epidemiology of vectorborne diseases. In addition, the center serves as the principal teaching resource for undergraduate and graduate courses in all facets of vector-borne disease sciences.