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Genome of Medieval Relapsing Fever Pathogen Provides Insights Into Microbe's Evolution

NEW YORK (GenomeWeb) – Researchers in Norway have pieced together the genome of a 15th-century pathogen that caused a type of relapsing fever, showing how genomic changes over the ages may have contributed to its ability to evade the human immune system.

Louse-borne relapsing fever (LBRF), caused by the spirochete Borrelia recurrentis, is thought to have killed millions of people over the course of European history.

While the disease is now rare in Europe, LBRF arises occasionally in Ethiopia, Eritrea, Somalia, and Sudan. It is marked by a fever, remission, and then relapse. If untreated, it is fatal in 10 to 40 percent of cases.

Researchers from the University of Oslo recovered B. recurrentis from a skeleton that was interred in a graveyard in Oslo between 1430 and 1465. As they reported in the Proceedings of the National Academy of Sciences today, they generated a genome assembly for the medieval pathogen, which they compared to reference genomes of related Borrelia species and strains obtained from East African refugees with LBRF.

"By comparing our medieval Borrelia recurrentis genome with modern representatives of the species, we offer a historical snapshot of genomic changes in an immune-evasion system and of reductive evolution in a specialized vector-borne human pathogen," senior author Barbara Bramanti from the University of Oslo and her colleagues wrote in their paper.

An initial metagenomic analysis of shotgun sequencing data obtained from the 15th-century individual — a woman between 28 and 35 years old when she died who was interred with a child — uncovered hits that matched B. recurrentis. Radiocarbon dating placed the skeleton to be from between 1430 AD and 1465 AD.

By mapping that shotgun sequencing data to the B. recurrentis reference genome, the researchers were able to recover nearly 17 percent of the B. recurrentis chromosome. The spirochete harbors one 1.24-megabase linear chromosome and seven linear plasmids.

To bolster their assembly, the researchers sequenced 13 additional libraries from two teeth. With that, they were able to assemble a B. recurrentis genome at a mean depth of 6.4X with 95.2 percent of its genome covered at least twice. They reported assembling 98.2 percent of the main chromosome to a mean depth of 8.3X.

The researchers compared their medieval B. recurrentis genome to six recently published de novo assemblies from samples obtained from East African refugees with relapsing fever. The East African strains, the researchers noted, had an approximately 40-kilobase extension at the 5' end of pl124 and a 1-kilobase reduction at the 3' end of pl6, similar to the corresponding plasmids in B. duttonii and B. crocidurae.

As the 15th-century B. recurrentis also had a longer pl124 and shorter pl6, compared to the reference, the researchers suggested that the reference genome might be incompletely assembled.

Meanwhile, the researchers found that the medieval strain lacked three variable short protein (vsp) genes typically found on the 3' ends of three separate plasmids and that one plasmid also lacked variable long protein (vlp) genes.

These genes encode surface lipoproteins that act as the main proinflammatory proteins of B. recurrentis, the researchers noted. The proteins are thought to be responsible for the relapsing nature of LBRF as they enable the expression of different variants of antigenic surface proteins, allowing the pathogen to evade the host immune system. The researchers hypothesized that these differences in vlp and vsp genes between the medieval and modern strains may have led to a difference in phenotype: recent clinical reports suggest patients may experience up to five relapses of LBRF, while historical texts mention only one or two relapses.

At the same time, they noted an overall reduction of 1.2 percent in the pan-genome and between 5.1 and 21 percent in the plasmids.

"Our results illustrate the potential of ancient DNA research to elucidate dynamics of reductive evolution in a specialized human pathogen and to uncover aspects of human health usually invisible to the archaeological record," the researchers wrote.