More than 500 years ago, most of the Aztecs were wiped out from the face of the Earth by a terrible epidemic. Scientists now think they know what killed them.

In 1545, following the arrival of Spanish settlers in modern-day Mexico and some parts of Guatemala, diseases started to spread among both natives and invaders. In total, 20 million people died following a first outbreak in 1545 and a second in 1576.

One of these diseases was particularly fatal to the Aztecs, killing 80% of their population – 15 million people – in less than 5 years. The mysterious disease was called 'cocoliztli' by locals.

The symptoms of the illness ranged from high fevers to bleeding from the mouth, eyes and nose, followed by, after three to four days of suffering, death.

The sheer number of victims makes this epidemic the second deadliest in modern history, after the Black Death (bubonic plague), which killed 25 million people in Western Europe during the 14th Century.

Cocoliztli translates to "pestilence" in the Aztec language. However, even after more than 500 years of speculation, the actual disease's pathology has not been accurately identified.

On Monday (15 January), scientists ruled out some other possible conditions, including smallpox, measles, mumps, and influenza. "The cause of this epidemic has been debated for over a century by historians and now we are able to provide direct evidence through the use of ancient DNA to contribute to a longstanding historical question," said Ashild Vagene of the University of Tuebingen in Germany, who researched this subject.

Using DNA samples extracted from 29 well-conserved dead bodies buried with other cocolizlti victims, the research team found that the Aztecs might have died from a form of typhoid fever.

Typhoid is a form of enteric fever usually associated with a salmonella strain called Salmonella Enterica. This bacterium causes enteric fevers like typhoid fever. While it scarcely infects humans today, the strain was deadly to the Aztecs, whose immune systems were not ready to defend themselves against the diseases brought by Spanish settlers. According to Vagene's research, the strain spread through food and the animals the Spanish colony had brought with them from Europe.

Cases of Salmonella Enterica were indeed reported in Western Europe in the 15th, which consolidates Vagene's team's findings.

There might be more to cocoliztli than meet the eye, though. The research team says it is possible other pathogens have remained undetected or "completely unknown." However, the team believe that Salmonella Enterica "is a strong candidate."

"There is a natural temptation – which the authors of this study admirably resist – to try and find a single linear cause for events," Dr Caroline Dodds Pennock, lecturer in International History at the University of Sheffield, told IBTimes UK.

"This study gives us one interesting piece of the puzzle, but the big picture, of cultures and families being assailed from all sides by death and disease, tells a much more complex and horrifying story."

Vagene and his co-authors' findings were published in Nature Ecology and Evolution.