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Where No Botulinum Toxin Has Gone Before

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Posted February 5, 2018

Enterococci are hardy microbes that thrive in the gastrointestinal tracts of nearly all land animals, including our own, and generally cause no harm. But their ruggedness has lately made them leading causes of multi-drug-resistant infections, especially in settings like hospitals where antibiotic use disrupts the natural balance of intestinal microbes.

So the discovery of a new toxin in a strain of Enterococcus is raising scientific eyebrows. Isolated from cow feces sampled at a South Carolina farm, the bug was unexpectedly found to carry a toxin resembling the toxin that causes botulism. The finding was reported in Cell Host and Microbe.

“This is the first time a botulinum neurotoxin has been found outside of Clostridium botulinum—and not just the toxin, but an entire unit containing the toxin and associated proteins that prevent the toxin from being degraded in the GI tract,” said Min Dong, Harvard Medical School assistant professor of surgery at Boston Children’s Hospital and one of the world’s experts on botulinum toxins.

The toxin, dubbed BoNT/En, is the ninth botulinum toxin to be described. Last August, Dong and colleagues reported the eighth, BoNT/X, made by C. botulinum—the first new botulinum toxin to be found in close to 50 years.

Should we be scared?

No. At least, not yet, said Sicai Zhang, a postdoctoral fellow in Dong’s lab and one of three co-first authors on the new report.

“The enterococcal isolate carrying the toxin luckily remains susceptible to key antibiotics,” said Zhang. “It was found only once from a single animal, and no signs of botulism disease were observed.”

When Sicai and his colleague Jie Zhang tested the toxin in rodents in the lab, it had little or no effect. Only when they manipulated the toxin to better target mouse and rat neurons did it become potent, shutting down nerve function and causing paralysis.

Dong’s lab is now testing BoNT/En in cultured human neurons to find out whether it’s toxic to humans.

Making the leap

How could this botulinum toxin jump from one bacterial species to another? Teams led by Dong’s collaborators, Michael Gilmore, the HMS Sir William Osler Professor of Ophthalmology at Massachusetts Eye and Ear, and Andrew Doxey, a bioinformatician at the University of Waterloo, found that the BoNT/En botulinum toxin genes were carried by a plasmid.

Plasmids are mobile structures that contain DNA independently of chromosomes and can be swapped from one bacterium to another. Plasmids are quite common in enterococci. In fact, they have been associated with the acquisition of resistance to vancomycin, a last-resort antibiotic, and transfer of resistance to the fearsome Staphylococcus aureus.

Down on the farm

Gilmore’s lab sequenced the toxin producing E. faecium strain as part of a much wider search for the origins of enterococcal antibiotic resistance and disease-causing ability.

“We were not looking for a neurotoxin in E. faecium,” said Francois Lebreton, HMS instructor of ophthalmology at Mass. Eye and Ear and another co-first author on the paper, who specializes in examining the genome sequences of these microbes. “There was no reason to suspect its existence.”

Source:HMS

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