NEW YORK (GenomeWeb) – Harboring a certain human leukocyte antigen allele made medieval leprosy patients more susceptible to infection with Mycobacterium leprae.
During the Middle Ages in Europe, leprosy was a common, chronic infectious disease marked by lesions, skin growths, and numbness, and afflicted people were often shunned by society. While leprosy is far less common now in Europe, researchers are not certain why that is, as the bacterium that causes the disease has not changed much over time, which in turn suggests host factors could play a role in disease predisposition.
A team of German and Danish researchers isolated both M. leprae and human DNA from infected medieval skeletons buried in Denmark for analysis and comparison against modern samples. As they reported today in Nature Communications, the team found that the HLA allele DRB1*15:01 among medieval people was associated with a predisposition to leprosy, just as it is among modern populations.
"The comparison of genotype data from 69 M. leprae DNA-positive cases with those from contemporary and medieval controls revealed a statistically significant association in both instances," researchers led by Kiel University's Almut Nebel wrote in their paper.
Previous studies among modern populations found that the HLA allele DRB1*15:01 is a risk factor for lepromatous leprosy, a severe form of the disease. In this study, Nebel and her colleagues isolated ancient DNA from remains with signs of lepromatous leprosy from a cemetery at the St. Jørgen leprosarium in Odense, Denmark, that dates back to between 1270 AD and 1550 AD.
The researchers also tested the samples for the presence of M. leprae to find that all 69 samples contained that bacterial DNA. For 10 of the samples, the researchers isolated enough M. leprae DNA for de novo assembly. They reported that these samples did not seem to harbor any changes that would suggest a change in virulence or function.
The researchers noted that Sanger sequencing of the DRB1 exon among their human samples was not feasible in ancient DNA, so they relied on genotyping their samples using the SNP allele rs3135388-T that has served as a marker for DRB1*15:01. PCR-based Sanger sequencing for the SNP allele found that 69 of the 85 St. Jørgen samples had enough DNA for genotyping.
Using the genotyping data, the researchers conducted an association test using the St. Jørgen samples as cases and a cohort of modern northern Germans as controls. They reported that the rs3135388-T allele was more common in the cases as compared to those controls. In subsequent testing using 152 ancient individuals from medieval sites in Denmark and northern Germany, the St. Jørgen cases still were enriched for the allele compared to the medieval controls.
The researchers noted that the rs3135388-T allele was slightly less common among modern populations than among ancient populations, indicating that there could be weak selection against the allele.
HLA typing of the samples further found that the rs3135388-T did co-occur with the DRB1*15:01.
But, Nebel and colleagues noted that the DRB1*15:01 allele is still found among Europeans. They reported that it is predicted to bind to a small number of M. leprae antigens, which they said might lead to ineffective antigen presentation and limited specific immunity against M. leprae.
In addition, the researchers noted that all individuals with the DRB1*15:01 also had the DRB1*06:02 allele, which is a risk factor for ulcerative colitis, sarcoidosis, and multiple sclerosis, but is protective against type 1 diabetes. This, they said, highlights the pleiotropy of HLA variants that affects their population frequency.
"[O]ur findings provide a new, temporal layer of evidence for the hypothesis that ancient epidemics such as leprosy have influenced the present-day frequency of genetic factors associated with modern inflammatory diseases," the researchers wrote.