A mysterious epidemic that killed millions of people in 16th century Mexico may be linked to a rare strain of Salmonella, a new DNA analysis reveals. The discovery is the best clue yet to the cause of a devastating infection that killed up to 80 percent of Mexico’s native population between 1545 and 1550 — spreading to Guatemala, and possibly as far south as Peru.

At the time, no one had ever seen anything like this disease: it made its victims bleed from their faces. Medical texts from the period show stacks of corpses and people speckled by rashes, gushing blood from their noses. Indigenous peoples called it “huey cocoliztli,” or great pestilence. Spanish invaders named it “pujamiento de sangre,” which translates to abundant bleeding or full bloodiness. Now, after analyzing the DNA trapped in human remains, a team of scientists have a new name to throw into the mix: a rare strain of the Salmonella enterica bacteria called Paratyphi C, the team reports today in the journal Nature Ecology & Evolution.

The symptoms of Paratyphi C, which is spread by food and water contaminated by human poop, match historical reports of fever, rash, stomach pain, and intestinal bleeding. The researchers can’t say for certain that this microbe caused the devastating epidemic. But 10 of the 24 bodies unearthed from a mid-16th century Mexican cemetery tested positive for the bacteria, making this a likely suspect — especially since a widespread drought at the time could have harmed sanitation.  

“We were all very happy to be able to find something, because a lot of the time the DNA just doesn’t preserve,” says Åshild Vågene, an archaeogeneticist at the Max Planck Institute for the Science of Human History in Germany and lead author of the study. “For us to find 10 in 24 is actually really cool.”

The cemetery was one of two uncovered during excavations led by Nelly Robles Garcia, national coordinator of archaeology for the National Institute of Anthropology and History in Mexico. One of the cemeteries is older, where people were buried before Europeans landed in the New World. The other dates to the mid-1500s, right around the time when Europeans first entered the region. Both are located at a site called Teposcolula-Yucundaa, which sits perched on a mountain ridge in southern Mexico. Once home to the indigenous Mixteca people, the Spanish forced the site’s remaining population to relocate after the 1545–1550 epidemic.

Working with researchers at Harvard University, scientists at the Max Planck Institute investigated the remains of five bodies excavated from the pre-contact cemetery, and 24 bodies buried at the post-contact cemetery. The researchers cracked open the teeth, and extracted DNA from the pulpy, blood vessel-rich tissue inside that was protected through the centuries by the enamel. When it comes finding fragile, ancient DNA, Vågene says, “We really thought this was our best bet of finding anything.”

After sequencing the soup of human and microbial DNA trapped inside the teeth, the researchers then had to sort out which strings of genetic code came from which organisms. So they used an algorithm that takes each piece of the code and holds it up against known microbial genomes — searching for matches. Stretches of DNA from three of the teeth clearly matched up against the Salmonella enterica genome. And of the Salmonella strains in the database, Paratyphi C was the best match.

Once the team knew what they were looking for, it became easier to spot the traces of Paratyphi C DNA. They found it in 10 individuals buried at the post-contact cemetery, but none at the pre-contact cemetery or soil samples from the site (except for one soil sample that was likely contaminated). That means the bacteria probably wasn’t local to southern Mexico — and had to have come from somewhere, possibly Europe. There are hints that Paratyphi C was in Europe as early as 1200 CE, according to a study posted on the pre-print server bioRxiv that has not yet been peer reviewed.

The team does a solid job linking Paratyphi C to this epidemic, says Hendrik Poinar, an ancient DNA expert at McMaster University who wasn’t involved in the research. There were certainly other diseases circulating at the time that could have killed people in similar ways — on their own or by working together with Paratyphi C. “It’s always hard to rule other things out,” Poinar says in an email to The Verge. Other microbes may not preserve well, or might not be present in the blood at high enough levels to be detected. Still, he says, “I think the paper is really nice work!”

Vågene agrees that there’s still more work to be done, including investigating other sites in Mexico and Central America for traces of Paratyphi C. “We haven’t solved it yet,” she says. “I would say that we’ve added a piece to the puzzle.”