Bubonic plague may be deadlier than its benign cousin because of two small tweaks to its genetic blueprint, new research suggests.

The bubonic plague bacterium, Yersinia pestis, has killed more than 200 million people, while its ancestor Yersinia pseudotuberculosis is usually harmless. The two diverged a mere 20,000 years ago, implying that only a few genetic changes made Y. pestis lethal, says Ronald Viola, a chemistry professor at the University of Toledo in Ohio. Researchers also noticed that harmful species of the genus Yersinia made nonfunctional versions of an enzyme called aspartase, while less infectious Yersiniae created functional forms. Aspartase breaks down the amino acid aspartic acid.

Viola and his colleagues compared the aspartase genes of Y. pestis and Y. pseudotuberculosis. He and his colleagues found the pair were identical except for changes to two base pairs, the building blocks of the genetic code, they report in the May issue of Microbiology.

To see whether these changes made the enzyme nonfunctional, the researchers substituted the mutations found in Y. pestis into Y. pseudotuberculosis. The swap made aspartase nonfunctional in Y. pseudotuberculosis. Conversely, replacing both mutations in the plague bacteria with base pairs found in its cousin restored the enzyme's function, says Robert Brubaker, a microbiologist at the University of Chicago who was involved in the study. Repairing either mutation on its own did not fix the enzyme, Viola says.

The researchers don't know how an influx of aspartic acid could make plague so deadly, but they have some ideas. To survive at human body temperature, plague bacteria depend on plentiful supplies of calcium. But relatively little free calcium floats around inside the body. To adjust to these conditions of scarcity, Y. pestis does a metabolic switcharoo, changing to a pathway that cranks out more aspartic acid than the human body can handle. So plague may wreak havoc by making the cells more acidic, Viola says.

“You are putting the host in a position where it would have to reverse its normal amino acid metabolism to accommodate this extra aspartate, and that could be the final straw that breaks the camel’s back,” Brubaker says.

To verify the link between aspartic acid breakdown and disease, the researchers need to show that restoring the function of the aspartase enzyme in the plague bacteria makes it less harmful in mammals like guinea pigs, Brubaker says.

Rodents like prairie dogs and gerbils are the primary host for the bacteria, and currently only a few thousand people worldwide contract bubonic plague each year, comments Olaf Schneewind, a microbiology professor at the University of Chicago who also studies Y. pestis. One in seven of these people die in the United States, and 50 to 60 percent of those not treated with antibiotics die. Even though the disease no longer ravages humans as it once did, “it's not a threat that ever goes away, so mankind needs to be prepared for another epidemic,” Schneewind adds.

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