Abstract Salmonella enterica serovar Paratyphi C is the causative agent of enteric (paratyphoid) fever. While today a potentially lethal infection of humans that occurs in Africa and Asia, early 20 th century observations in Eastern Europe suggest it may once have had a wider-ranging impact on human societies. We recovered a draft Paratyphi C genome from the 800-year-old skeleton of a young woman in Trondheim, Norway, who likely died of enteric fever. Analysis of this genome against a new, significantly expanded database of related modern genomes demonstrated that Paratyphi C is descended from the ancestors of swine pathogens, serovars Choleraesuis and Typhisuis, together forming the Para C Lineage. Our results indicate that Paratyphi C has been a pathogen of humans for at least 1,000 years, and may have evolved after zoonotic transfer from swine during the Neolithic period. One Sentence Summary The combination of an 800-year-old Salmonella enterica Paratyphi C genome with genomes from extant bacteria reshapes our understanding of this pathogen’s origins and evolution.

Millennia of genomic stability within the invasive Para C Lineage ofSalmonella enterica