Cocoliztli, a Nahuatl word meaning “pest” or “pestilence,” refers to a series of devastating epidemics that struck 16th-century Mexico, killing millions of Indigenous people in what ranks among the worst demographic catastrophes in recorded history. For centuries, the cause remained a mystery, with candidates ranging from smallpox to plague to an unknown hemorrhagic fever. Then, in 2018, a team of researchers extracted ancient DNA from the teeth of epidemic victims buried in southern Mexico and identified a surprising culprit: Salmonella enterica Paratyphi C, a bacterium that causes enteric fever. That finding reframed one of the great unsolved questions of colonial-era epidemiology, though it also raised new questions about how a single pathogen could produce such staggering mortality.
The Scale of the Catastrophe
Two major waves of cocoliztli swept through Mexico, in 1545 and again in 1576. The earlier outbreak struck roughly a generation after the Spanish conquest and killed an enormous but poorly documented number of people. The 1576 epidemic left a clearer paper trail because Spanish colonial administrators had recently conducted censuses. Researchers who analyzed data from the 1570 and 1580 censuses across 157 districts found that the total population in those communities fell from about 2.1 million to just over 1 million, a loss of 51.36%.1PubMed Central. When half of the population died: the epidemic of hemorrhagic fevers of 1576 in Mexico Contemporary observers at the time estimated that roughly two million people died across the country, and the census data appear to confirm those estimates were not exaggerated.2FEMS Microbiology Letters. When half of the population died: the epidemic of hemorrhagic fevers of 1576 in Mexico
One of the most striking features of the epidemic was its ethnic selectivity. Spanish colonists living in the same regions were minimally affected, while Indigenous communities suffered catastrophic mortality.1PubMed Central. When half of the population died: the epidemic of hemorrhagic fevers of 1576 in Mexico This pattern long fueled speculation that the disease was something the Indigenous population had never encountered before, leaving them immunologically defenseless. It also complicated identification of the pathogen, because European diseases like smallpox and measles, while devastating to Indigenous peoples, did not typically produce the specific constellation of symptoms colonial-era physicians described.
What Victims Actually Experienced
Colonial-era accounts describe cocoliztli as horrific in its presentation. Victims suffered from hemorrhagic bleeding, gangrene, jaundice, delirium, convulsions, and dysentery.3University Press of Colorado. Indian autopsy and epidemic disease in early colonial Mexico The range and severity of these symptoms puzzled generations of historians and epidemiologists. Hemorrhagic bleeding, for instance, is not characteristic of enteric (typhoid-like) fever, which more typically involves prolonged high fever, abdominal pain, and intestinal complications. This mismatch between the historical symptom descriptions and the pathogen eventually identified through DNA is one reason the cocoliztli debate is not fully settled.
Some researchers have argued that the hemorrhagic symptoms point toward a viral hemorrhagic fever, possibly carried by rodents native to Mexico. Others suggest the symptom descriptions may have been exaggerated or conflated with other concurrent diseases. In a population already weakened by famine, forced labor, and social disruption, a severe enteric fever could have produced unusual and extreme symptoms. The truth is that 16th-century medical accounts, written by observers using a completely different framework for understanding disease, are imperfect diagnostic tools.
How Ancient DNA Cracked the Case
The breakthrough came from an epidemic-era cemetery at Teposcolula-Yucundaa, a Mixtec community in the highlands of Oaxaca. Researchers applied a metagenomic screening tool called MALT to DNA extracted from the teeth of individuals buried at the site during the 1545 epidemic. Tooth pulp is an especially useful tissue for this kind of work because bloodborne pathogens become trapped in the dental pulp during systemic infection and are then sealed inside the durable enamel structure. The team identified Salmonella enterica subspecies enterica serovar Paratyphi C in ten individuals and reconstructed genome-wide data from those ancient bacterial sequences.4PubMed. Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico
Salmonella Paratyphi C causes enteric fever, a systemic illness in the same family as typhoid. Modern enteric fever, caused predominantly by Salmonella Typhi and Paratyphi A, still causes roughly 12 to 25 million cases worldwide each year with about a 1% mortality rate, primarily through contaminated food and water.5ScienceDirect. Hunter’s Tropical Medicine and Emerging Infectious Diseases (Tenth Edition) – Chapter 74: Typhoid and Paratyphoid (Enteric) Fever Paratyphi C, however, is extremely rare today. Its identification in a 16th-century mass burial site was unexpected and suggested the pathogen once played a far larger epidemiological role than its current obscurity would imply.
Subsequent work has refined the tools used for authenticating ancient pathogen DNA. A pipeline called HOPS was developed specifically to automate the screening and authentication of ancient bacterial sequences, helping researchers distinguish genuine ancient infections from modern contamination or environmental bacteria.6PubMed Central. HOPS: automated detection and authentication of pathogen DNA in archaeological remains This kind of rigorous verification matters enormously when the claim involves identifying a specific pathogen from fragments of DNA that have been degrading underground for nearly five centuries.
Where Did the Pathogen Come From
If Salmonella Paratyphi C caused cocoliztli, a natural follow-up question is whether the bacterium was already present in the Americas or was brought by European colonizers. The evidence increasingly points toward a European introduction. A 17th-century genome of Paratyphi C was recovered from a Spanish soldier who died during the siege of Barcelona in 1651–1652. Phylogenetic analysis placed this European strain in a position basal to the diversity observed in post-contact Mexican strains, meaning the Mexican lineages appear to have branched off from an older European lineage rather than the other way around. The estimated split between the Spanish and Mexican strains was dated to the early 14th century, before Columbus.7iScience. A 17th-century Salmonella enterica Paratyphi C genome from a Spanish soldier deployed at the siege of Barcelona (1651–1652)
More recent genomic work, still in preprint, has added further detail. A study analyzing ancient Paratyphi C genomes from central Mexico estimated that the Mexican and European lineages shared a common ancestor roughly 1,400 years ago, well before European colonization. However, the divergence between one central Mexican strain and the southern Mexican genomes from Teposcolula-Yucundaa occurred only about 516 years ago, coinciding closely with the arrival of Spanish colonizers. The researchers interpret this pattern as supporting a European introduction of the pathogen during colonization, followed by local diversification within Mexico.8bioRxiv. Ancient genomic insights into Salmonella enterica Paratyphi C from Central Mexico
The picture that emerges is of a pathogen circulating in Europe, where populations had long exposure and some degree of acquired immunity, being carried to the Americas and encountering a population with no prior experience of enteric Salmonella infections. Europeans, who had been living with the bacterium for centuries, would have experienced far lower mortality, consistent with the observed ethnic selectivity of cocoliztli.
Drought, Famine, and the Perfect Storm
A pathogen alone does not explain the extraordinary death toll. The cocoliztli epidemics occurred during what climate scientists have identified as a 16th-century megadrought, a period of severe and prolonged dry conditions that extended from central Mexico to the boreal forests of Canada and from the Pacific coast to the Atlantic.9PubMed. Drought, epidemic disease, and the fall of classic period cultures in Mesoamerica (AD 750-950). Hemorrhagic fevers as a cause of massive population loss Tree-ring data have confirmed that the 1545 and 1576 outbreaks coincided with extreme drought conditions.10PubMed Central. Megadrought and megadeath in 16th century Mexico
Drought affects waterborne disease in counterintuitive ways. When water sources shrink, the remaining supply becomes more concentrated with contaminants. People are forced to use water sources they would normally avoid. And when rains do return after prolonged drought, the resulting runoff can flush accumulated waste and pathogens into drinking water supplies. Research on waterborne disease outbreaks in the United States between 1948 and 1994 found that over half of all outbreaks were preceded by extreme precipitation events, with the strongest associations for surface water contamination.11PubMed Central. The association between extreme precipitation and waterborne disease outbreaks in the United States, 1948-1994 A cycle of drought punctuated by sudden heavy rains would have been ideal for spreading a fecal-oral pathogen like Salmonella.
On top of the drought, Indigenous communities were enduring the cascading disruptions of colonization: forced relocation, destruction of traditional agricultural systems, compulsory labor in mines and on Spanish estates, and the psychological and nutritional toll of subjugation. Malnutrition compromises immune function, and crowded labor conditions facilitate disease transmission. The epidemic did not arrive in a vacuum. It hit a population that was already under extraordinary stress, and the drought ensured that the most basic public health safeguard, clean water, was in short supply.
Why the Debate Is Not Over
The identification of Paratyphi C was a landmark finding, but it has not ended the argument. Several legitimate objections keep the question partially open.
First, there is the symptom mismatch already described. The hemorrhagic features colonial physicians documented do not fit neatly with enteric fever as it presents today. Defenders of the Salmonella hypothesis argue that a naive population encountering the pathogen for the first time, under conditions of severe malnutrition and dehydration, could have experienced atypical and more severe disease. Skeptics counter that hemorrhagic fevers caused by viruses, possibly rodent-borne, remain a plausible alternative. The tree-ring evidence for drought aligns with both hypotheses, since drought can concentrate rodent populations around remaining water sources, increasing human-rodent contact.10PubMed Central. Megadrought and megadeath in 16th century Mexico
Second, the ancient DNA evidence comes from a single cemetery at one site in Oaxaca. While the results are compelling, a sample from one location cannot definitively represent an epidemic that swept the entire country. It is possible that Paratyphi C was present at Teposcolula-Yucundaa while a different pathogen, or multiple pathogens, drove mortality elsewhere. The preprint findings from central Mexico strengthen the case by identifying the same organism in a geographically distinct location, but the evidence base remains small relative to the scale of the epidemic.
Third, and perhaps most fundamentally, ancient DNA has inherent blind spots. Both Gram-negative bacteria (the category that includes Salmonella) and RNA viruses degrade rapidly after death, making them harder to detect in archaeological remains. RNA viruses are especially fragile because RNA molecules break down far more quickly than DNA.12Current Biology. Ancient Pathogen Genomics: The Hindsight and Foresight of Past Pathogens This means that if a viral pathogen was also circulating during the cocoliztli outbreaks, whether as a co-infection or as the primary killer, ancient DNA methods might never detect it. The discovery of Salmonella proves its presence but does not rule out other pathogens that leave no recoverable genetic trace.
The Evolutionary History of an Obscure Pathogen
One of the more fascinating threads emerging from the cocoliztli research is what it reveals about the evolutionary history of Salmonella Paratyphi C itself. Today, Paratyphi C is a clinical rarity, overshadowed by Typhi and Paratyphi A as causes of enteric fever. But ancient genomic studies suggest it was once widespread. A medieval genome of a related Salmonella strain recovered from Norway showed that about 78% of the roughly 4,400 genes in the Paratyphi C lineage genome were intact core genes, with only 604 core-level genetic differences separating that ancient strain from the ancestor of modern Paratyphi C.13Current Biology. Salmonella enterica Genomes from Sources in Norway, the Americas, and Europe Provide a Reassessment of the Evolutionary History of the Para C Lineage The pathogen’s genome has been remarkably stable over long periods, and its presence across medieval Europe and colonial-era Mexico indicates it once had a much broader geographic and epidemiological footprint.
What caused Paratyphi C to fade into near-irrelevance while Typhi and Paratyphi A persisted? The answer likely involves improvements in water and sanitation infrastructure, changes in animal husbandry (Paratyphi C can infect pigs, giving it a potential animal reservoir), and possibly the rise of competing Salmonella serovars that outcompeted it ecologically. But the full story remains unclear, and the cocoliztli research has put Paratyphi C back on the map as a pathogen whose past significance was dramatically underestimated.
A Genetic Scar on Living Populations
The epidemics did not just reduce the population. They reshaped the genetic makeup of the survivors and their descendants. Genomic analysis of Indigenous populations in southern Mexico has confirmed that Mesoamerican peoples went through a severe population bottleneck during the colonial period. Effective population size dropped by roughly an order of magnitude, from tens of thousands to low single-digit thousands, between about 375 and 200 years ago, a timeline that aligns with the colonial-era epidemics and their aftermath.14Genome Biology and Evolution. The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans
More telling than the bottleneck itself is what researchers found when they looked at which genes showed signs of recent natural selection in these populations. Immune-related genes, particularly those involved in the major histocompatibility complex and a signaling pathway called PPAR-γ, showed strong signatures of directional selection, meaning certain variants were being favored and pushed to higher frequency in the population.14Genome Biology and Evolution. The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans In plain terms, the epidemics were so severe and so selective that they functioned as a filter on the human genome: those who survived carried immune variants that were better suited to fighting the pathogens they had encountered, and those variants became more common in subsequent generations.
This genetic legacy has real implications today. Variation in immune-related genes can influence susceptibility to infections, autoimmune conditions, and inflammatory diseases. The colonial-era epidemics did not just shape the past. They left a molecular signature that continues to influence the health of Indigenous Mexican populations centuries later, a reminder that the line between historical event and living biology is thinner than it appears.
When One Health Meets Ancient Disease
The cocoliztli story has also become a case study for the “One Health” approach, the framework that recognizes that human health, animal health, and the environment are deeply interconnected. The identification of Paratyphi C was guided partly by ecological reasoning: the pathogen can circulate in animals, particularly pigs, and its spread depends on environmental conditions like water quality and sanitation infrastructure.15Pathogens and Disease. The One Health Concept—the Aztec empire and beyond The arrival of European livestock in the Americas brought new animal reservoirs into contact with Indigenous communities that had no prior exposure to the pathogens those animals carried.
From this perspective, cocoliztli was not simply a disease event. It was an ecological collision. European colonizers brought their domestic animals, their microbes, and their land-use practices to a continent where the existing equilibrium between people, animals, and pathogens was entirely different. When you add drought stress to that already destabilized system, the result was a public health catastrophe of almost unimaginable proportions. The fact that we can now reconstruct pieces of this story from bacterial DNA trapped in teeth for five centuries is a testament to how far the science has come, but it is also a humbling reminder of how much ancient DNA cannot tell us about the full complexity of what happened.