Plague existed 3,300 years earlier than previously thought

Plague existed during the Bronze Age, and infections were common in humans 3,300 years earlier than previously thought, says research published in Cell.

DNA tests on teeth show that plague existed in the Bronze Age, which is earlier than previously believed.
Image credit: Rasmussen et al./Cell 2015

But it took at least 1,000 more years for the bacterium to undergo key genetic changes that enabled the disease, Yersinia pestis (Y. pestis), to spread via fleas and evade the host immune system.

Y. pestis was the notorious culprit behind the 6th century's Plague of Justinian, the Black Death, which killed 30-50% of the European population in the mid-1300s, and the Third Pandemic, which devastated China in the 1850s. A small number of cases occur every year in the US, mostly in the rural west.

The Plague of Athens, nearly 2,500 years ago, and the 2nd century's Antonine Plague, have been linked to the decline of Classical Greece and the undermining of the Roman army.

However, it was not known whether Y. pestis was responsible for these early epidemics, because there was no direct molecular evidence for this bacterium from skeletal material older than 1,500 years.

To investigate, researchers from the Center for GeoGenetics at the University of Copenhagen in Denmark examined the DNA of tooth samples from Bronze Age individuals from Europe and Asia, discovering evidence of plague infections roughly 4,800 years ago.

Based on these findings, researchers from the University of Gothenburg in Sweden and collaborators suspected that the plague could have affected human populations much earlier than previously thought.

Did ancient epidemics shape Europe's population?

The researchers had already published a high-profile population genomics study of Eurasian individuals from the Bronze Age (c. 3000-1500 BC), a highly dynamic period featuring large-scale migrations and population replacements that shaped major parts of present-day demographic structure in Europe and Asia.

What caused these migrations was a mystery. The team suggested large epidemics: people escaping from diseases or moving to places emptied of population by some plague. Could it have been the Black Death?

To find out, they screened 89 billion raw DNA sequence reads from the teeth of 101 Bronze Age individuals from Europe and Asia, obtained from museums and archeological excavations.

They discovered Y. pestis DNA in seven individuals, dated between 2794 BC and 951 BC (early Iron Age). Evolutionary analysis revealed the most recent common ancestor of all known Y. pestis strains to be 5,783 years old, thousands of years earlier than previously thought.

Yet in Bronze Age times, the plague was not yet able to spread widely; what happened in the Iron Age? 

Secrets of the plague's success

Two factors explain the spread: one relates to the immune system, the other, transmissibility.

Fast facts about plague

• The last urban plague in the US was in Los Angeles from 1924-25
• An average of 7 cases are reported in the US each year
• In 2014, the US saw 10 cases and no fatalities.

Earlier forms of the plague were susceptible to the immune system. Older traces show the presence of the protein flagella, the whip-like appendage that helps bacteria move around. In mammals, the immune system recognizes flagella and fights it.

Bronze Age Y. pestis still featured flagella, making it easier for the immune system to detect and defeat it. By the Iron Age, a genetic mutation had led to the loss of the flagella, enabling the plague to avoid detection.

Secondly, Y. pestis genomes had not yet developed a gene called Yersinia murine toxin (ymt), which protects the pathogen inside the flea gut, thereby enabling the spread of plague to humans through an insect vector.

By the Iron Age, 3,700-3,000 years ago, the ymt gene had evolved. It protected Y. pestis in the guts of rats, making it fully transmissible by fleas.

Thus, Y. pestis seems to have adapted fully as a flea-borne mammalian pathogen around 1,000 BC, giving rise to the historically recorded plagues.

The researchers found that the Y. pestis lineage originated and was widespread much earlier than previously thought, and we narrowed the time window as to when it developed. This study changes our view of when and how plaque influenced human populations and opens new avenues for studying the evolution of diseases.

It now seems that this extremely important human pathogen could have been responsible for earlier plagues, such as the Plague of Athens and the Antonine Plague.

The research team plans to search for evidence of plague and other blood-borne bacteria and viruses in further geographic regions and time periods.

They note that the underlying evolutionary mechanisms that made the evolution of Y. pestis possible still exist today; they hope the work will increase understanding of how future pathogens may arise or become more virulent.

We have learned from a report earlier this year that rats in the New York City subway could transmit bubonic plague.

References:

1. Early divergent strains of Yersinia pestis in Eurasia 5,000 years ago, Rasmussen et al., Cell, doi.org/10.1016/j.cell.2015.10.009, published 22 October 2015 abstract.
2. Cell Press news release, accessed 21 October 2015.
3.  Additional source: Centers for Disease Control and Prevention (CDC), Plague in the United States, accessed 21 October 2015.