Ancient DNA Study in Medieval Europeans Shows an Association Between HLA-DRB1*03 and Paratyphoid Fever

Abstract

Outbreaks of infectious diseases repeatedly affected medieval Europe, leaving behind a large number of dead often inhumed in mass graves. Human remains interred in two burial pits from 14th century CE Germany exhibited molecular evidence of Salmonella enterica Paratyphi C (S. Paratyphi C) infection. The pathogen is responsible for paratyphoid fever, which was likely the cause of death for the buried individuals. This finding presented the unique opportunity to conduct a paratyphoid fever association study in a European population. We focused on HLA-DRB1*03:01 that is a known risk allele for enteric fever in present-day South Asians. We generated HLA profiles for 29 medieval S. Paratyphi C cases and 24 contemporaneous controls and compared these to a modern German population. The frequency of the risk allele was higher in the medieval cases (29.6%) compared to the contemporaneous controls (13%; p = 0.189), albeit not significantly so, possibly because of small sample sizes. Indeed, in comparison with the modern controls (n = 39,689; 10.2%; p = 0.005) the frequency difference became statistically significant. This comparison also suggested a slight decrease in the allele’s prevalence between the medieval and modern controls. Up to now, this is the first study on the genetic predisposition to Salmonella infection in Europeans and the only association analysis on paratyphoid fever C. Functional investigation using computational binding prediction between HLA variants and S. Paratyphi and S. Typhi peptides supported a reduced recognition capacity of bacterial proteins by DRB1*03:01 relative to other common DRB1 variants. This pattern could potentially explain the disease association. Our results suggest a slightly reduced predisposition to paratyphoid fever in modern Europeans. The causative allele, however, is still common today, which can be explained by a trade-off, as DRB1*03:01 is protective against infectious respiratory diseases such as severe respiratory syndrome (SARS). It is thus possible that the allele also provided resistance to corona-like viruses in the past.

Ancient DNA study provides clues to leprosy susceptibility in medieval Europe

“…However, the development of the aDNA technology allows for such analyses to be performed in past populations [16,44,87,88]. This study demonstrates the tremendous potential of this methodology in the identi cation of genetic variants involved in predisposition to infectious diseases that are no longer present in Europe but remain endemic in other parts of the world.…”

“…To date, it is the rst ancient DNA association study in which variation at six HLA loci were examined in the context of leprosy susceptibility in the medieval European population. It is also one of very few disease association studies performed in past populations [16,44].…”

Historic and Prehistoric Epidemics: An Overview of Sources Available for the Study of Ancient Pathogens

“…The Para C lineage likely arose in Neolithic Europe from pig Salmonellae [ 79 , 187 ], and has thus been able to maintain its virulence in humans over millennia. It is, however, less prevalent at present, which could be partly due to host genetic selection, for instance at the HLA-DRB1 locus [ 188 , 189 ]. The secondary major historical pathogens, at least in Europe, proved to be louse-borne microbes, namely the agents of epidemic typhus, trench fever, relapsing fever, and possibly plague, which has been speculated to have also been transmitted by lice [ 71 ].…”

Historic and Prehistoric Epidemics: An Overview of Sources Available for the Study of Ancient Pathogens

“…The Para C lineage likely arose in Neolithic Europe from pig Salmonellae [75,181], and has thus been able to maintain its virulence in humans over millennia. It is, however, less prevalent at present, which could be partly due to host genetic selection, for instance at the HLA-DRB1 locus [182,183]. Next major historical pathogens, at least in Europe, proved to be louse-borne microbes, namely the agents of epidemic typhus, trench fever, relapsing fever, and possibly plague, which has been speculated to have been transmitted by lice, too [67].…”