It was one of the most devastating epidemics in human history. The 1545 outbreak, and a second wave in 1576, killed an estimated 7 million to 17 million people and contributed to the destruction of the Aztec Empire. But identifying the pathogen responsible for the carnage has been difficult for scientists because infectious diseases leave behind very little archaeological evidence. “There have been different schools of thought on what this disease was. Could it have been plague? Could it have been typhoid fever? Could it have been a litany of other diseases?” says Kirsten Bos, a molecular paleopathologist at the Max Planck Institute in Germany, and an author of a new study published Monday in Nature Ecology and Evolution. The study analyzes DNA from the teeth of 10 people who died during the epidemic and pinpoints a possible culprit: a type of salmonella that causes a deadly fever. A new algorithm allowed Bos and her team to identify fragments of ancient salmonella DNA with extreme specificity. “It was an analytical technique that was really the game-changer for us,” Bos explains. While scientists have been able to extract ancient DNA from bones and other tissue, until recently it was impossible to compare that extracted DNA to a wide variety of potential matches. But a new computer program called MALT allowed them to do just that. “The major advancement was this algorithm,” Bos says. “It offers a method of analyzing many, many, many small DNA fragments that we get, and actually identifying, by species name, the bacteria that are represented.” Bos and her team used MALT to match up the DNA fragments extracted from teeth of epidemic victims with a database of known pathogens. The program didn’t entire save them from mind-numbing work — at one point PhD student and study author Ashild Vagene had to go through the results of the program by hand. In the end, they found evidence of the deadly Salmonella enterica Paratyphi C bacteria. The study does not pinpoint the source of the bacteria, which is an area of great interest for biologists and archaeologists alike. The authors note that many epidemics of the period are believed to originate with European invaders who arrived in the region in the early part of the 16th century, but the new research doesn’t present biological evidence for or against that. Salmonella enterica gemones from victims of a major sixteenth-century epidemic in Mexico Nature Ecology and Evolution, Published online 15 January 2018, Åshild J. Vågene, Alexander Herbig, Michael G. Campana, Nelly M. Robles García, Christina Warinner, Susanna Sabin, Maria A. Spyrou, Aida Andrades Valtueña, Daniel Huson, Noreen Tuross, Kirsten I. Bos & Johannes Krause, doi:10.1038/s41559-017-0446-6 https://www.nature.com/articles/s41559-017-0446-6 Indigenous populations of the Americas experienced high mortality rates during the early contact period as a result of infectious diseases, many of which were introduced by Europeans. Most of the pathogenic agents that caused these outbreaks remain unknown. Through the introduction of a new metagenomic analysis tool called MALT, applied here to search for traces of ancient pathogen DNA, we were able to identify Salmonella enterica in individuals buried in an early contact era epidemic cemetery at Teposcolula-Yucundaa, Oaxaca in southern Mexico. This cemetery is linked, based on historical and archaeological evidence, to the 1545–1550 CE epidemic that affected large parts of Mexico. Locally, this epidemic was known as ‘cocoliztli’, the pathogenic cause of which has been debated for more than a century. Here, we present genome-wide data from ten individuals for Salmonella enterica subsp. enterica serovar Paratyphi C, a bacterial cause of enteric fever. We propose that S. Paratyphi C be considered a strong candidate for the epidemic population decline during the 1545 cocoliztli outbreak at Teposcolula-Yucundaa.Rebecca Hersher of NPR reports that in 1545, people in the Mexican highlands starting dying in enormous numbers. People infected with the disease bled and vomited before they died. Many had red spots on their skin.