Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster


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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Figure 1: De novo genome assemblies and phylogenetic reconstruction.
Figure 2: Median-joining (MJ) network analysis and geographic distribution of the SS14 and Nichols clades.


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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




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.

Corresponding authors

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

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Methods; Supplementary Tables 3, 5, 6, 9, 10; Legends for all Supplementary Tables; Supplementary Figures 1-6; Supplementary References. (PDF 820 kb)

Supplementary Table 1

Sample Information. (XLSX 14 kb)

Supplementary Table 2

Read preprocessing, mapping and genotyping results. (XLSX 23 kb)

Supplementary Table 4

SNP calls for samples used in genome-wide data analyses (n = 39). (XLSX 14 kb)

Supplementary Table 7

Putative recombinant genes identified by Gubbins and ClonalFrameML. (XLSX 16 kb)

Supplementary Table 8

Clade classification and mutations associated with antibiotic resistance (for all sequenced and published samples). (XLSX 12 kb)

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Arora, N., Schuenemann, V., Jäger, G. et al. Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster. Nat Microbiol 2, 16245 (2017). https://doi.org/10.1038/nmicrobiol.2016.245

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