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# Genome Yields Clues to Tsetse Fly's Strange and Deadly Ways

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Science  25 Apr 2014:
Vol. 344, Issue 6182, pp. 349-350
DOI: 10.1126/science.344.6182.349

A tsetse fly bite feels like a hammer blow. Smaller than horse flies but more aggressive, these African insects also carry trypanosome parasites responsible for sleeping sickness and the cattle disease nagana, two scourges of sub-Saharan Africa. Chemical traps and aerial spray programs targeting tsetse flies have replaced cruder control methods—inspectors at car checkpoints used to swat any flies they saw on dashboards. But 70 million Africans are still at risk for sleeping sickness, which causes extreme lethargy and can be fatal, and an estimated 3 million farm animals die each year from nagana.

Now, the first sequenced genome of a tsetse fly species, Glossina morsitans, may prime the pump for better control efforts. On page 380, and in 11 satellite papers in Public Library of Science (PLOS) journals, a collaboration called the International Glossina Genome Initiative (IGGI) reveals hints of what makes tsetse flies so successful and how the disease-causing trypanosomes interact with the flies that carry them. "Understanding the biology of the tsetse fly is an essential step to fight the disease and limit its diffusion," says Philippe Bastin, a parasitologist at the Institut Pasteur in Paris.

Most people think of mosquitoes as bloodsuckers, but they pale in comparison with tsetse flies, arguably the vampires of the insect world. Whereas mosquitoes also sip nectar and only the females suck blood, one tsetse fly can drink almost its weight in blood each meal, and both sexes consume nothing else. The fly needs a special repertoire of proteins for procuring, filtering, and packaging blood, as well as resident bacteria to provide nutrients not found in blood. Researchers are also eager to understand the genes and proteins underlying another tsetse fly oddity: They bear live young—one at a time—and nourish the developing larva with "milk" secreted from special glands.

The new genome is still in many pieces, but Serap Aksoy and Geoffrey Attardo of Yale University and their colleagues have already discerned 12,300 protein-coding genes. The research team also surveyed gene activity in various tissues, such as the salivary glands, which trypanosomes use as a launching point for infecting their next hosts, and milk glands, to see what proteins were important.

With its narrow blood diet, the tsetse fly doesn't need the full range of taste and odor receptors found, for example, in fruit flies, says Daniel Masiga, a molecular biologist at the International Centre of Insect Physiology and Ecology in Nairobi. He and his colleagues uncovered what appear to be 46 tsetse proteins sensitive to odors (the fruit fly has 58) and just 14 proteins for taste (the fruit fly has 73), with none sensitive to sugar. The fly also has fewer genes for proteins that recognize pathogens—possibly because its restricted diet exposes it to fewer infectious threats. The tsetse fly has more proteins for detecting carbon dioxide, however, likely useful for finding mammalian quarry through their exhalations.

Once a tsetse fly bites a victim, 250 proteins in its saliva work to keep blood from coagulating and to protect against the bitten host's immune system, among other things. But the team found that a trypanosome interferes with this efficient feeding machine—likely to its own benefit. With the parasite in its salivary glands, the fly produces fewer of these proteins, making feeding less efficient and forcing it to bite more often. That "will favor transmission" of the parasite, Bastin says.

To cope with its diet, the fly has an unusually large number of genes for proteins called aquaporins, which move water between cells. When those genes are knocked out, the tsetse fly has trouble excreting the bolus of water in ingested blood, has lower heat tolerance, and spends a longer time pregnant, the initiative reports in PLOS Neglected Tropical Diseases. Some aquaporin genes are particularly active in the milk gland and may be important in formulating milk, the researchers note. The genome also contains eight newly discovered milk protein genes, and a paper in PLOS Genetics reports that when a female is lactating, those genes and other associated milk gland genes rev up their activity 40-fold and account for half of the fly's total gene activity.

As part of the tsetse fly genome project, Aksoy's collaborator, Matthew Berriman of the Wellcome Trust Sanger Institute in Hinxton, U.K., also sequenced the DNA of some of the insect's resident microbes. One that had been previously sequenced, Wigglesworthia glossinidia, is a bacterium that lives in a specialized organ in the insect's gut and helps keep it well nourished. The microbe, for example, has genes for the synthesis of vitamin B, whereas the tsetse has only proteins for transporting this vitamin. "Without these obligate microbes, the fly cannot maintain fecundity," Aksoy says.

IGGI hopes the tsetse fly sequence will help revive the long-stalled fight against the insect and the misery it spreads. Even though epidemics of sleeping sickness erupted in the 1980s and 1990s, the number of researchers studying the host tsetse fly sharply declined during that period, with many switching to the better funded fields of malaria and AIDS. Beginning in 2004, Aksoy and the few remaining researchers in the field established the initiative on a shoestring—about $50,000 per year from the World Health Organization. Then in 2006, the Wellcome Trust committed about$4 million in in-kind sequencing toward decoding one tsetse fly species. All told, 146 researchers helped decipher the new genome.

No vaccines against trypanosome diseases now exist, and the available drugs cause severe side effects including convulsions. One control strategy that seeks to get rid of tsetse flies by flooding the population with sterile males is showing some success (Science, 20 July 2007, p. 310). But better control strategies are needed. The new genome suggests one: Chemical inhibitors targeting the single transcription factor that controls milk protein production could inhibit tsetse fly fecundity and lower parasite transmission rates. And now that researchers know the tsetse fly's repertoire of taste and odor receptors, they should be able to improve traps by including more attractive chemical baits. "This is really going to drive research in how to control tsetse flies in the next 2 decades," says Stephen Richards, an arthropod genomicist at Baylor College of Medicine in Houston, Texas.

However, researchers studying malaria and other insect-transmitted diseases caution that translating genome data into control strategies is difficult. Najib El-Sayed, a parasitologist at the University of Maryland, College Park, has sequenced several parasite genomes, and each time he expected that cures for their associated diseases or ways to prevent their spread would be forthcoming in 5 years. "Now I know better," he says. "The genome is just the beginning."

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