Treponema pallidum infections occur worldwide causing, among other diseases, syphilis and yaws. In particular sexually transmitted syphilis is regarded as a re-emerging infectious disease with millions of new infections annually. Here we present three historic T. pallidum genomes (two from T. pallidum ssp. pallidum and one from T. pallidum ssp. pertenue) that have been reconstructed from skeletons recovered from the Convent of Santa Isabel in Mexico City, operational between the 17th and 19th century. Our analyses indicate that different T. pallidumsubspecies caused similar diagnostic presentations that are normally associated with syphilis in infants, and potential evidence of a congenital infection of T. pallidum ssp. pertenue, the causative agent of yaws. This first reconstruction of T. pallidum genomes from archaeological material opens the possibility of studying its evolutionary history at a resolution previously assumed to be out of reach.
Among the worldwide prevalent treponemal diseases syphilis is a global threat that is currently re-emerging. The origins of syphilis and other treponemal diseases are as yet unresolved and are subject to an intensive scholarly debate. Until now, assumptions on its origins and evolutionary history could only be drawn from osteological analyses of past cases and genetic analysis of contemporary T. pallidum genomes; contributions from ancient DNA are very rare and have so far failed to provide genome-level data. The ancient T. pallidum genomes presented here allow us, for the first time, to perform genome-wide comparative analyses and to assess a connection between osteological manifestations of past treponemal cases and specific T. pallidum species. Our study demonstrates the possibility of retrieving ancient T. pallidum genomes from archeological material and thereby establishes a new method that could greatly contribute to uncover the mystery regarding the origins of treponemal diseases.
Treponema pallidum subspecies cause several diseases, among which sexually transmitted syphilis, caused by T. pallidum ssp. pallidum (TPA), and yaws, caused by T. pallidum ssp. pertenue (TPE), are the best known and are prevalent worldwide. The global disease burden is high for both diseases. Syphilis is seen as re-emerging in various regions of the world including Europe, North America, China and Australia  with 10.6 million cases reported in 2009 , while for yaws more than 300,000 new cases were recorded between 2008 and 2012 . The origins and evolutionary history of these pathogens remain nebulous, including the perceived sudden appearance and pandemic spread of syphilis in Europe at the end of the 15th century. Hypotheses surrounding the origin of syphilis are subject to an extensive scholarly debate, in particular the New World origin of syphilis with worldwide dissemination starting in the 15thcentury [4, 5] in contrast to the hypothesis of multiregional origin that posits an increase in virulence followed by a pandemic spread in the 15th century . While genetic data from contemporary T. pallidum strains has been interpreted as support for the New World origin [7, 8], there exists potential skeletal evidence in support of the multiregional origin [9, 10], yet this remains heavily debated [11, 12].
Ancient DNA could help to resolve this controversy by illuminating the evolutionary history of human-pathogenic treponemes. However, detection of ancient treponemal DNA is very rare. To date, only short strain-unspecific PCR fragments have been retrieved from a 200-year-old mummy  and from European post-Columbian neonates . Furthermore, even in modern patients with advanced stage syphilis, who may display bone lesions, molecular detection of the bacterium is challenging  casting doubt on the possibility of a successful recovery of T. pallidum from ancient skeletons . Our latest research on non-human treponemes, however, was successful in retrieving T. pallidum ssp. pertenue DNA from non-human primate bones that were several decades old .
Here, we use DNA hybridization capture methods in combination with high-throughput sequencing to retrieve historic T. pallidum DNA (T. pallidum ssp. pallidum and T. pallidum ssp. pertenue) and to successfully reconstruct three genomes using bone material dating back to Colonial Mexico with characteristic skeletal manifestations for congenital treponematosis . Our study establishes the possibility of retrieving ancient T. pallidum genomes from archeological material and allows us, for the first time, to assess the genomic principle of past treponemal infections.
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