Abstract

The abrupt onslaught of the syphilis pandemic that started in the late fifteenth century established this devastating infectious disease as one of the most feared in human history1. Surprisingly, despite the availability of effective antibiotic treatment since the mid-twentieth century, this bacterial infection, which is caused by Treponema pallidum subsp. pallidum (TPA), has been re-emerging globally in the last few decades with an estimated 10.6 million cases in 2008 (ref. 2). Although resistance to penicillin has not yet been identified, an increasing number of strains fail to respond to the second-line antibiotic azithromycin3. Little is known about the genetic patterns in current infections or the evolutionary origins of the disease due to the low quantities of treponemal DNA in clinical samples and difficulties in cultivating the pathogen4. Here, we used DNA capture and whole-genome sequencing to successfully interrogate genome-wide variation from syphilis patient specimens, combined with laboratory samples of TPA and two other subspecies. Phylogenetic comparisons based on the sequenced genomes indicate that the TPA strains examined share a common ancestor after the fifteenth century, within the early modern era. Moreover, most contemporary strains are azithromycin-resistant and are members of a globally dominant cluster, named here as SS14-Ω. The cluster diversified from a common ancestor in the mid-twentieth century subsequent to the discovery of antibiotics. Its recent phylogenetic divergence and global presence point to the emergence of a pandemic strain cluster.

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Acknowledgements

Research in Zurich by N.A. and H.C.B. was funded by the Forschungskredit and the University of Zurich. A.H. was funded by an ERC Starting Grant. F.G.C. and L.S.B. were funded by MINECO (Spanish Government) and PROMETEO (Generalitat Valenciana). K.I.B. was funded by the Social Sciences and Humanities Research Council of Canada. L.M. was funded by the Faculty of Medicine of Masaryk University. The authors thank S. Lautenschlager for guidance, A. Drummond for input on BEAST, S. Lukehart for providing HaitiB, Sea86-1, Bal3, Bal9, Bal73-1 and Grady1 strain DNA, and C. Marra for providing UW249B and UW231B strain DNA. The authors also thank A. Messina and the S3IT at the University of Zurich for providing computational resources and services, and I. Schoechli and L. Keller's group for their valued support.

Author information

Author notes

    • Alexander Peltzer
    • , Alexander Herbig
    • , Kirsten I. Bos
    • , Leyla Rivero Davis
    • , Johannes Krause
    •  & Homayoun C. Bagheri

    Present address: Department of Archaeogenetics, Max Planck Institute for the Science of Human History, D-07745 Jena, Germany (A.P., A.H., K.I.B., J.K.); Department of Infectious Disease Epidemiology, Imperial College London, London SW7 2AZ, UK (L.R.D.); Repsol Technology Center, 28935 Mostoles, Madrid, Spain (H.C.B.).

Affiliations

  1. Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland

    • Natasha Arora
    • , Leyla Rivero Davis
    •  & Homayoun C. Bagheri
  2. Zurich Institute of Forensic Medicine, University of Zurich, 8057 Zurich, Switzerland

    • Natasha Arora
  3. Institute for Archaeological Sciences, University of Tübingen, 72070 Tübingen, Germany

    • Verena J. Schuenemann
    • , Alexander Peltzer
    • , Alexander Herbig
    • , Kirsten I. Bos
    •  & Johannes Krause
  4. Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany

    • Günter Jäger
    • , Alexander Peltzer
    • , Alexander Seitz
    • , Alexander Herbig
    •  & Kay Nieselt
  5. Department of Biology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic

    • Michal Strouhal
    • , Linda Grillová
    • , Lenka Mikalová
    •  & David Šmajs
  6. Unidad Mixta Infección y Salud Pública FISABIO/Universidad de Valencia; CIBER in Epidemiology and Public Health, 46020, Spain

    • Leonor Sánchez-Busó
    •  & Fernando González-Candelas
  7. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK

    • Leonor Sánchez-Busó
  8. Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich, 8092 Zurich, Switzerland

    • Denise Kühnert
  9. Department of Infectious Diseases, Public Health Laboratory, GGD Amsterdam, 1018 WT Amsterdam, the Netherlands

    • Sylvia Bruisten
  10. Department of Dermatology, Medical University of Graz, A-8036 Graz, Austria

    • Peter Komericki
  11. The Mortimer Market Centre CNWL, Camden Provider Services, London NW1 2PL, UK

    • Patrick French
  12. Department of Clinical Microbiology and Virology, University College London Hospitals NHS Foundation Trust, London W1T 4EU, UK

    • Paul R. Grant
  13. Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, 1121 Buenos Aires, Argentina

    • María A. Pando
  14. Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Microbiología Clínica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina

    • Lucía Gallo Vaulet
    •  & Marcelo Rodríguez Fermepin
  15. Servicio de Dermatología, Hospital General Universitario de Valencia, 46014 Valencia, Spain

    • Antonio Martinez
  16. Department of Medicine, Division of Allergy and Infectious Diseases, and Department of Global Health, University of Washington, Seattle, Washington 98105, USA

    • Arturo Centurion Lara
    •  & Lorenzo Giacani
  17. Department of Pathology and Laboratory Medicine, UTHealth McGovern Medical School, Houston, Texas 77225, USA

    • Steven J. Norris
  18. Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland

    • Philipp P. Bosshard

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Contributions

N.A. and H.C.B. conceived the investigation. N.A., L.G., S.J.N., D.S., P.P.B., F.G.-C., K.N., J.K. and H.C.B. devised research and analyses. N.A., G.J., A.P., A.S., A.H., M.S., L.G., L.S.-B., D.K., L.R.D., L.M., F.G.-C. and K.N. analysed data. N.A., V.J.S., M.S., L.G., K.I.B., L.R.D., L.G.V. and P.P.B. contributed to or performed experiments. M.S., L.G., S.B., P.K., P.F., P.R.G., M.A.P., L.G.V., M.R.F., A.M., D.S., P.P.B. and F.G.-C. provided clinical samples and A.C.L., L.G., S.J.N. and D.S. provided laboratory samples. N.A. and H.C.B. wrote the manuscript with significant contributions from M.S., L.G., L.S.-B., D.K., K.I.B., L.R.D., L.M., S.B., L.G., S.J.N., D.S., P.P.B., F.G.-C., K.N. and J.K. and with comments from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Natasha Arora or Fernando González-Candelas or Kay Nieselt or Johannes Krause or Homayoun C. Bagheri.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Methods; Supplementary Tables 3, 5, 6, 9, 10; Legends for all Supplementary Tables; Supplementary Figures 1-6; Supplementary References.

Excel files

  1. 1.

    Supplementary Table 1

    Sample Information.

  2. 2.

    Supplementary Table 2

    Read preprocessing, mapping and genotyping results.

  3. 3.

    Supplementary Table 4

    SNP calls for samples used in genome-wide data analyses (n = 39).

  4. 4.

    Supplementary Table 7

    Putative recombinant genes identified by Gubbins and ClonalFrameML.

  5. 5.

    Supplementary Table 8

    Clade classification and mutations associated with antibiotic resistance (for all sequenced and published samples).