Assaulting the mosquito’s sense of smell

The mosquito may be nature’s most effective bioterrorist, accounting for millions of deaths each year. But the end of its eons’ long reign of terror may be in sight. Scientists have begun to apply the power of genomics and molecular biology to understand how the mosquito detects the subtle chemical cues that lead it to its targets. “The mosquito is the most dangerous animal on the planet. It relies on its sense of smell to find the source of its blood meals. So understanding how its olfactory system works at the molecular level should suggest new and novel ways to keep it from spreading catastrophic diseases,” says Laurence J. Zwiebel, assistant professor of biological sciences at Vanderbilt. His laboratory is the first to have identified the genes that code for proteins, called odorant receptors, which are a key part of the mosquito’s olfactory system. These proteins extend outside olfactory neurons and, when they come into contact with specific chemicals in the form of odors, initiate the cascade of electrochemical events that produce the sense of smell.

Writing in the Nov. 27 issue of the online version of the Proceedings of the National Academy of Sciences, Zwiebel and his colleagues at Vanderbilt, the University of Illinois, Urbana-Champaign and Yale University report isolating four genes from the genome of Anopheles gambiae – an African mosquito that feeds primarily on humans and spreads malaria – that are extremely similar to genes generally considered to code for odorant receptors in the fruit fly Drosophila, which serves as a scientific model for insects. The researchers also determined that these genes are only expressed in the mosquito’s antennae and maxillary palps, which serve a role similar to the nose.

There is a general misconception that mosquitoes pick prey based on the taste of their blood. Actually, previous studies have shown that mosquitoes are primarily attracted by body odor and other emissions such as carbon dioxide. “We all produce a cloud of chemicals and mosquitoes can track the odor trail that we leave for quite a distance,” says Zwiebel. Many of these chemical cues are created by the bacteria that cover our bodies. Studies have shown that fewer mosquitoes attack a person after they have taken a shower. If the person showers with anti-bacterial soap, the number drops even further.

Despite the large evolutionary distance between man and mosquito, at the molecular level both are equipped with basically the same chemosensory system. “Ever since evolution figured out how to sense different chemicals, it has kept the same molecular switches and machinery. The system in your nose and my nose recapitulates that found in insects,” says Zwiebel.

The fact that the olfactory system is so highly conserved helped the researchers identify the A. gambiae odorant receptor genes. They found four potential genes by scanning the six percent of the mosquito genome that was then available for sequences that looked similar to odorant receptor genes found in Drosophila. Once they identified the genes, they were able to determine that all four were only expressed in the antennae and maxillary palps that are part of its olfactory system and not in any other tissues. In the fruit fly some 60 receptor genes are involved in olfaction, so Zwiebel and his colleagues expect to find about the same number in the mosquito. Furthermore, the researchers were able to show that one of the newly identified odorant receptors appears to be associated with the blood feeding patterns of the female A. gambiae. In mosquitoes, it is only the female that is responsible for biting people and spreading disease. The female needs blood to reproduce. Previous studies have found that for about 72 hours after feeding, female mosquitoes don’t respond as strongly to human odors as they do normally. Suggestively, the Vanderbilt group found that one of the new receptors is expressed only in female antennae and exhibits decreased expression levels during this post-feeding period. The researchers hope that these kinds of discoveries will eventually suggest new and effective ways to keep mosquitoes from preying on people that will be less poisonous than the insecticide and repellent sprays now in common use. For example, a compound might be found that reduces the mosquitoes’ response to human odors. “Of course, the obvious goal is to make effective repellents. There is a widespread need for a good mosquito repellent,” says Zwiebel. There are other possible approaches as well. If a potent mosquito attractant could be found, it could be used to lure them into a container filled with a potent insecticide.

“Molecular biology provides a new arrow in the quiver of both high and low tech methods that the World Health Organization and other groups are using to combat this scourge,” says Zwiebel. Vanderbilt University has filed for a patent on the newly discovered genes because there is considerable commercial interest. While malaria has been largely eliminated in industrialized countries like the United States, there is still considerable interest in mosquito repellant sprays, and recent outbreaks of West Nile fever indicate that the threat of mosquito-borne diseases cannot be ignored.

In addition, the highly conserved nature of the olfactory system means that similar approaches are likely to work in other insects that pose threats as agricultural pests. So research of this sort may ultimately lead to ways to reduce insect damage to crops and stored food, along with a number of other useful applications.

In addition to Zwiebel, collaborators on the study are A. Nicole Fox, a graduate student, and R. Jason Pitts, a research associate, both in the Zwiebel laboratory, and Hugh M. Robertson of the University of Illinois at Urbana-Champaign and John Carlson at Yale University.

The research was funded by the World Health Organization, the National Science Foundation and the National Institutes of Health.

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