Ancient genomic insights into Salmonella enterica Paratyphi C from Central Mexico

Salmonella enterica is a widespread pathogen of major global health relevance, with over 2,500 serovars classified into non-typhoidal and typhoidal groups. Within the typhoidal group, S. enterica Paratyphi C causes paratyphoid fever in humans. Ancient DNA from this bacterium has previously been recovered from epidemic-associated burials in Eurasia and Mexico, dating back 6,000 to 300 years. Here, we analyzed dental DNA from seven individuals (radiocarbon dated to 1800–1940 CE) buried at the Temple of the Immaculate Conception in Mexico City, Central Mexico, and identified ancient S. enterica Paratyphi C DNA in a young female with Native American ancestry. Using an in-house targeted enrichment strategy and deep shotgun sequencing, we reconstructed a S. enterica Paratyphi C genome (COYC5) with ∼11X coverage. Phylogenetic and comparative genomic analyses place COYC5 in close association with previously reported S. enterica Paratyphi C genomes associated with the 1545 cocoliztli epidemic in southern Mexico, as well as with European strains. Divergence estimates indicate that the Mexican and European lineages shared a common ancestor approximately 1,400 years before present (yBP), reflecting an ancient evolutionary split predating European colonization of Mexico. In contrast, the divergence between COYC5 and the southern Mexican genomes occurred around 516 yBP, coinciding with the onset of the colonial period. This pattern supports a European introduction of S. enterica Paratyphi C during colonization, followed by its local diversification within Mexico. Despite this regional differentiation, the conserved presence of key virulence loci—such as SPI-7 and an active shufflon system—across COYC5, southern Mexican, and European genomes underscores the enduring pathogenic potential of S. enterica Paratyphi C. The identification of this bacterium in 19th-century Mexico City provides the first genomic evidence of its persistence in urban contexts beyond major epidemic outbreaks, offering new insights into its evolutionary trajectory in Mexico. These findings raise new questions about how the pathogen spread and persisted across different ecological, social, and epidemiological contexts in ancient Mexico and the Americas.