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03_28_05

If They Can’t Smell Us, They Can’t Bite Us

For most people, small biting insects are merely irritating. However, they can also be deadly. The bite of the female Anopheles gambiae mosquito spreads malaria, which kills more than a million people each year worldwide. Malaria is also a major cause of death for children in developing nations.

Although there is currently no vaccine in widespread use to prevent malaria infection, research has led to several effective methods to control the disease. Some of these include bed netting, insecticides, and drugs that act on the active and inactive mosquito-transmitted parasites that cause disease once an individual is already infected. Unfortunately, the malaria causing parasites found in areas of the world where infection is widespread are becoming resistant to many currently available drugs. Thus, researchers are desperately searching for new ways to prevent and/or treat malaria.

NIDCD-supported research is developing an innovative approach to stop the spread of malaria. The idea is based upon the discovery that female Anopheles mosquitoes, which prefer to feed upon human beings, have a receptor to a specific compound found in human sweat. This receptor enables the mosquito to smell human sweat and target its victims. If scientists can somehow block or inactivate this receptor, the mosquitoes would no longer be able to smell human sweat, and thus would not seek to bite us. If successful, this innovative approach may help break the cycle of malaria transmission.

The Road to Discovery. But how were scientists able to identify the human sweat receptor in malaria-spreading mosquitoes? What led them to believe that such a receptor even existed? The road leading to this groundbreaking discovery begins at least 15 years ago, in NIDCD-supported labs studying the sense of smell in another insect, the common fruit fly Drosophila melanogaster.

Drosophila melanogaster is an ideal model for studying the sense of smell, or olfaction. Drosophila olfactory systems are simple, yet they function similarly to those of other organisms. The genome of Drosophila has been sequenced, providing fertile starting material for identifying olfactory genes. Scientists can measure the response to an odor in a living fly, either by observing its behavior or by recording electrical currents from one or more of its smell-detecting neurons. Finally, Drosophila’s role as a classical organism of choice for genetic manipulations has led to development of powerful tools to study individual gene function. All of these characteristics make Drosophila a useful tool for identifying genes important for olfaction.

In 1989, NIH-supported scientists identified a Drosophila mutant with a specific defect in its ability to detect the odor of benzaldehyde. The flies responded normally to other odors, suggesting that there may be olfactory pathways dedicated to detecting specific odors or related families of odors. Subsequent studies by the same scientists identified and described a molecular pathway inside odor-detecting cells [the inositol 1, 4, 5-triphosphate (IP3) pathway] that helps transmit a chemical message indicating that an odor has been detected. Because IP3 pathways usually interact with cell surface receptor proteins, the NIDCD-supported scientists began to search for such receptors in the Drosophila olfactory system. In 1999, they published a report describing how they had developed and used a novel search algorithm on the Drosophila genomic sequence database to find potential olfactory receptor proteins. Their search yielded a large multigene family of receptors located in exactly the right place to serve as odor receptors: embedded in the membranes of olfactory receptor neurons.

From Flies to Mosquitoes. Because olfaction plays a major role in insect behavior, genes important for detecting odors are often conserved across insect species. Thus, the Drosophila lab collaborated with another group of NIDCD-supported researchers to search for odorant receptors in the mosquito that transmits malaria, Anopheles gambiae. In 2001, the collaborative group reported that they had identified four genes in Anopheles that were expressed only in its olfactory system, suggesting that they code for mosquito olfactory receptors. They also noted another tantalizing detail: one of the putative receptor genes, AgOr1, was expressed only in the female olfactory system, and its expression was down-regulated after the mosquito had fed on human blood.

The scientists began to suspect that AgOr1 was the key. But how does this receptor lead the mosquito to target and bite human beings? Although their studies over the next three years uncovered important information about the molecular genetics of mosquito olfaction, the scientists were initially unable to link the AgOr1 to any of the odors known to attract Anopheles.

Mystery Solved at Last. Their breakthrough discovery was finally reported via a brief communication published in the January 15, 2004 edition of the journal Nature. The group determined that female Anopheles AgOr1 responds to a component in human sweat. At last, the mystery was solved! Mosquitoes detect the odor of human sweat and home in to feed. Researchers are now working to determine how to exploit this knowledge to help human beings: how can we interfere with the Anopheles’ ability to detect human sweat and thus prevent it from biting us?

NIDCD’s long-term investments in olfactory research first begun in Drosophila and now being studied in Anopheles mosquitoes are the foundation supporting the current new attempts to halt the spread of malaria. Preventing the bite that transmits malaria will eliminate the danger of drug-resistant infections by preventing infection in the first place. This story of discovery is another example of how basic scientific research in insects can have direct, practical and lifesaving applications for human beings.

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