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Research uncovers historical rise, fall and re-emergence of plague strains

Northern Arizona University

One branch of a deadly pathogen's family tree may have ended centuries ago, but from its ancient traces researchers can read a lineage with links to the modern world.

An international team of scientists has discovered that two of the world's most devastating pandemics--the plague of Justinian and the Black Death, each responsible for killing as many as half the people in Europe--were caused by distinct strains of the same pathogen.

The strain that helped bring an end to the Roman Empire faded out on its own about 1,500 years ago. But the other, which flourished 800 years later, led to worldwide re-emergence in the late 1800s and is still with us today, killing thousands each year.

The findings suggest a new strain of bubonic plague could emerge again in humans in the future.

"This is the oldest bacterial genome ever produced," said Dave Wagner, an associate professor in the Center for Microbial Genetics and Genomics at Northern Arizona University. "We were able to go back in time and find something that went extinct."

Wagner said the Justinian strain, which earlier research traced to having its origins in Asia, lies "smack between" two groups that are still found in China. "So that's pretty interesting that it moved all the way to Europe and went extinct. It could still be out there somewhere between Europe and China but we haven't seen it yet."

The plague of Justinian struck in the sixth century and is estimated to have killed between 30 million and 50 million people-- virtually half the world's population as it spread across Asia, North Africa, Arabia and Europe. The Black Death struck about 800 years later with similar force, killing 50 million Europeans between just 1347 and 1351 alone.

Researchers from NAU provided the overall plague expertise on the project, while those in the lab at McMaster University in Canada sequenced minuscule plague DNA fragments from the 1,500-year-old teeth of two victims of the Justinian plague, buried in Bavaria, Germany. The University of Sydney contributed expertise on the pathogen's molecular clock--a method used to infer when different events in the evolutionary history of a species have taken place. And colleagues from several institutions in Munich, Germany--including the State Collection for Anthropology and Paleoanatomy and the Bundeswehr Institute for Microbiology--provided the samples.

The team reconstructed the genome of the oldest strain of Yersinia pestis, the bacterium responsible for the bubonic plague, and compared it to a database of genomes of more than one hundred contemporary strains.

The results are currently published in the online edition of The Lancet Infectious Diseases. They show the strain responsible for the Justinian outbreak was an evolutionary 'dead-end' and distinct from strains involved later in the Black Death and other plague pandemics that would follow.

"The research is both fascinating and perplexing, it generates new questions which need to be explored," said Hendrik Poinar, associate professor and director of the McMaster Ancient DNA Centre and an investigator with the Michael G. DeGroote Institute for Infectious Disease Research. "For example, why did this pandemic, which killed somewhere between 50 and 100 million people, die out?"

The third pandemic, which spread from Hong Kong across the globe--including all the way to Arizona--is likely a descendant of the Black Death strain and thus was much more successful in evolutionary terms than the one responsible for the Justinian plague.

Although the rise and fall of the Justinian plague suggests that a similar emergence could happen again with a new strain, other factors render the scenario unlikely, Wagner said.

"We don't think we're going to see new large-scale plague pandemics. Not because the organism has changed--it's just as deadly as it always was--but humans have changed," Wagner said. Improvements in hygiene, particularly the limiting of rat populations in cities, and the emergence of antibiotics would limit the effective spread of the pathogen.

The samples used in the latest research were taken from two victims of the Justinian plague, buried in a gravesite in a small cemetery in the German town of Aschheim. Scientists believe the victims died in the latter stages of the epidemic when it had reached southern Bavaria.

The skeletal remains yielded important clues and raised more questions.

Researchers now believe the Justinian Y. pestis strain originated in Asia, not in Africa as originally thought. But they could not establish a 'molecular clock' so its evolutionary time-scale remains elusive.

This suggests that earlier epidemics, such as the Plague of Athens (430 BC) and the Antonine Plague (165 -180 AD), could also be separate, independent emergences of related Y. pestis strains into humans.

Our response to modern infectious diseases is a direct outcome of lessons learned from ancestral pandemics, say the researchers.

"This study raises intriguing questions about why a pathogen that was both so successful and so deadly died out," said Edward Holmes, an NHMRC Australia Fellow at the University of Sydney. "One testable possibility is that human populations evolved to become less susceptible,"

Wagner said another possibility is that "changes in the climate became less suitable for the plague bacterium to survive in the wild, or there was a lack of suitable rodent reservoirs."

Paul Keim, a Regents' Professor and the Cowden Endowed Chair of Microbiology at NAU said that "Plague has been circulating through civilization for at least 1500 years and characterizing this ancient genome allows us to understand how diseases arise and then spread from continent to continent - even to locations in Arizona."


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