In microbe’s genome, a potential target

As genomes go, the sequence of the lowly bacterium Wigglesworthia glossinidia doesn’t carry quite the clout of the human genome or even that of the mouse. But tiny as the bug’s gene collection may be—a mere 700,000 base pairs, compared to humans’ 3 million—it’s not at all trivial. Details of Wigglesworthia’s genetic code, deciphered by Yale’s Serap Aksoy, Ph.D., and co-workers and reported in the November 2002 issue of Nature Genetics, could lead to new approaches for dealing with a deadly disease that has been nearly impossible to control.

Wigglesworthia causes no illness itself. But in a complex, interdependent relationship that has evolved over the past 100 million years, the bacterium has come to live only in the gut of the tsetse fly. And it’s the blood-sucking tsetse fly that transmits a parasite responsible for sleeping sickness, a disease that caused severe epidemics in the last century and has been on the rise in southern Africa in recent years. An estimated 500,000 people currently have the disease, which is fatal without treatment with highly toxic drugs. Animals, too, are affected, with some 3 million head of livestock dying from the animal form of the disease every year. Infection of livestock has severely limited development and cattle raising in large parts of Africa.

“There are no vaccines and few effective drugs for treating sleeping sickness,” said Aksoy, an associate professor in the Division of Epidemiology of Microbial Diseases at the School of Public Health. “Vector control has been the major strategy employed for controlling the disease, and yet everything that’s being used for vector control is very inefficient and environmentally unsound. So it’s very crucial that we develop new approaches.”

That’s where Wigglesworthia could prove useful. Like many organisms, tsetse flies need vitamins to reproduce, but blood—their dietary mainstay—is notoriously low in vitamins. Previous research suggested that Wigglesworthia somehow helps supplement the fly’s diet, Aksoy said. “It was shown that if you eliminated the bacteria by antibiotic treatment, you aborted the fly’s fertility, and that supplementing with vitamins could restore fertility very slightly. That suggested that Wigglesworthia might be supplying vitamins to the fly, but no one really knew which vitamins or how extensive the requirement was.”

By decoding the Wigglesworthia genome, Aksoy and co-workers learned exactly which vitamins the bacterium produces for its host. They repeated the earlier experiments, first using antibiotics to clear Wigglesworthia from the flies and confirming that the flies became infertile, then supplementing the flies with the very vitamins that Wigglesworthia produces. This time, the flies’ fertility was fully restored.

The results suggest that finding ways to wipe out Wigglesworthia in the field might drastically reduce tsetse fly populations, helping to curb the spread of sleeping sickness.

“This opens a whole new avenue for us,” said Aksoy. “Before, the avenues for controlling the disease were based on targeting the parasite in the human or targeting its biology by interfering with insect functions, but now we have another target that we can aim at to reduce fly populations.”

Another observation Aksoy’s team has made in the lab underscores Wigglesworthia’s pivotal role. “We find that during their development in the fly, the parasites aggregate in very large numbers around the gut cells where Wigglesworthia live, suggesting that the parasites might also be obtaining nutrients from these bacteria,” said Aksoy. “Now we’re studying Wigglesworthia gene expression in both parasite-infected tsetse flies and uninfected flies, trying to understand what the bacteria might be provisioning to the developing parasites.”

In addition to Wigglesworthia, the researchers are studying two other bacteria that live in tsetse flies. The commensal Sodalis glossinidius also lives in the gut, and its genome sequence is near completion, while Wolbachia is found in the insect’s ovaries. “They’re all very compartmentalized, and they seem not to get in the way of one another in terms of tsetse biology, so we’re interested in how this all fits together—how the insect is able to maintain homeostasis or harmony, in association with all these bacteria.” In addition, Aksoy’s team is engineering Sodalis and Wolbachia to express foreign genes, in hopes of making tsetse flies resistant to infection with the disease-causing parasites.

“We’re hoping,” said Aksoy, “that eventually all of our studies with Wigglesworthia and the other bacteria will lead to novel control strategies whereby we can render tsetse flies incapable of parasite transmission.”