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Fuse of 'Vietnamese Time Bomb' Identified

10 November 2011 2:01 pm
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AAAS/Science

Tricky toxin. A protein called BPSL1549 (shown) could be Burkholderia pseudomallei's main tool for killing off animal cells.

Suave spy James Bond wields a lot of nefarious gadgets, from poison dart pens to laser-shooting watches. But a recently discovered protein belonging to the bacterium Burkholderia pseudomallei, the culprit behind the southeast Asian and northern Australian disease melioidosis, may be more deadly than them all. A new study suggests that this protein—dubbed BPSL1549—could make the bacterium 100 times more lethal than microbes engineered to stop making the toxin.

Melioidosis, also known as the "Vietnamese time bomb," received wide attention largely after the Vietnam War. As helicopters deposited troops throughout the tropical nation, their blades kicked up dirt, exposing soldiers and pilots to hidden pathogens in the soil. Melioidosis tends to cause a wide range of symptoms similar to other conditions, leading some scientists to give it the second nickname "the Great Mimicker." "You might look like you have some skin irritation, ... or you might have an abscess on your liver," says study co-author Stuart Wilson, a molecular biologist at the University of Sheffield in the United Kingdom. "And it's the same disease."

Many patients with melioidosis come down with a severe type of infection called, septicemia, says long-time melioidosis researcher Sharon Peacock of the University of Cambridge in the United Kingdom, who was not involved in this study. This bacterial assault is treatable with only a narrow range of antibiotics, she says, and in some locales, the death rates can be as high as 40%.

Combating the disease is tricky. Not only does it look like other diseases, but the B. pseudomallei bacteria are slow-growing, popping up days later than many microbes in lab cultures.

To combat this master spy, Wilson and his colleagues dug into its arsenal. The team spotted one suspicious-looking B. pseudomallei protein, BPSL1549, which, along a certain stretch of its structure, resembles an enzyme common in Escherichia coli bacteria. This E. coli protein is a cellular toxin, Wilson adds, that rapidly dismantles the molecular skeletons that support cells. The melioidosis bacterium's enzyme may also deal a death blow, researchers report online today in Science.

To observe the enzyme in action, Wilson and colleagues dosed mice with both normal B. pseudomallei bacteria and strains that didn't churn out dud versions of the BPSL1549 toxin. It took about 100 times more engineered bacteria to kill the rodents, he says, showing that while the microbe produces other poisons, BPSL1549 may be the worst.

When the group mixed the poisonous proteins with a range of molecules from human cells, they discovered that the bacterium's armaments didn't degrade cellular skeletons the way E. coli toxin does. Instead, the enzyme zeroes in on another target—a molecule called eIF4AI. That molecule plays a critical role in the assembly-line production of cellular proteins, Wilson says. When the bacterial toxin puts the kibosh on it, human cells are likely unable to churn out many of their building blocks. As far as spy gadgets go, this protein is a "potent" killer, he adds.

That's bad news for infected individuals but, potentially, good news for researchers. If scientists can find a counter-agent such as an antibody that turns off BPSL1549, they might be able to treat patients with melioidosis, Wilson says.

"The evidence from the paper does appear to be quite clear," says Peacock. Wilson's culprit seems to be responsible for much of B. pseudomallei 's deadly power, she says. And that could be an important revelation since the great mimicker could be more common than many thought. Scientists have spotted the bacterium as far away from Vietnam and Thailand as South America, she adds.

But potential drugs are also a long way off, cautions Herbert Schweizer, a microbiologist at Colorado State University, Fort Collins. Like most pathogens or secret agents, B. pseudomallei likely has a lot of gadgets up its sleeve. If scientists silence this one, he says, the bacteria could fall back on other, equally lethal weapons.

Correction: A previous version of this story suggested that the bacterial strain engineered by Wilson and his colleagues produced "faulty" or "dud" versions of the protein BPSL1549. These bacteria didn't produce the protein at all. The enzyme also zeros in on the molecule eIF4A1, not eLF4A1.

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