Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis

Mathew A. Beale; Michael Marks; Michelle J. Cole; Min Kuang Lee; Rachel Pitt; Christopher Ruis; Eszter Balla; Tania Crucitti; Michael Ewens; Candela Fernández-Naval; Anna Grankvist; Malcolm Guiver; Chris R. Kenyon; Rafil Khairullin; Ranmini Kularatne; Maider Arando; Barbara J. Molini; Andrey Obukhov; Emma E. Page; Fruzsina Petrovay; Cornelis Rietmeijer; Dominic Rowley; Sandy Shokoples; Erasmus Smit; Emma L. Sweeney; George Taiaroa; Jaime H. Vera; Christine Wennerås; David M. Whiley; Deborah A. Williamson; Gwenda Hughes; Prenilla Naidu; Magnus Unemo; Mel Krajden; Sheila A. Lukehart; Muhammad G. Morshed; Helen Fifer; Nicholas R. Thomson

doi:10.1038/s41564-021-01000-z

Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis

Mathew A. Beale^*, Michael Marks, Michelle J. Cole, Min Kuang Lee, Rachel Pitt, Christopher Ruis, Eszter Balla, Tania Crucitti, Michael Ewens, Candela Fernández-Naval, Anna Grankvist, Malcolm Guiver, Chris R. Kenyon, Rafil Khairullin, Ranmini Kularatne, Maider Arando, Barbara J. Molini, Andrey Obukhov, Emma E. Page, Fruzsina PetrovayCornelis Rietmeijer, Dominic Rowley, Sandy Shokoples, Erasmus Smit, Emma L. Sweeney, George Taiaroa, Jaime H. Vera, Christine Wennerås, David M. Whiley, Deborah A. Williamson, Gwenda Hughes, Prenilla Naidu, Magnus Unemo, Mel Krajden, Sheila A. Lukehart, Muhammad G. Morshed, Helen Fifer, Nicholas R. Thomson

^*Corresponding author for this work

UK Health Security Agency

Research output: Contribution to journal › Article › peer-review

75 Citations (Scopus)

Abstract

Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum, has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum, we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p.pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides.

Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.

Original language	English
Pages (from-to)	1549-1560
Number of pages	12
Journal	Nature Microbiology
Volume	6
Issue number	12
DOIs	https://doi.org/10.1038/s41564-021-01000-z
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
M.K. declares institutional funding from Roche, Hologic and Siemens, which is unrelated to this work. The remaining authors declare no competing interests. The funders had no input into the study design, interpretation or decision to submit for publication.

Funding Information:
We thank the sequencing team at the Wellcome Sanger Institute, and C. Puethe and the Pathogen Informatics team for computational support; additional technical staff involved in sample diagnostics, DNA extraction and sample retrieval in laboratories at Public Health England and NHS laboratories, UK; British Columbia CDC and Alberta Precision Laboratories, Canada; National Public Health Center, Budapest, Hungary; FRC Kazan Scientific Center, Tuva, Russia; National Institute for Communicable Diseases, Johannesburg, South Africa; Institute of Tropical Medicine, Antwerp, Belgium; Sahlgrenska University Hospital, Gothenburg, Sweden; Hospital Vall d’Hebron, Barcelona, Spain; Midlands Regional Hospital Portlaoise, Ireland; Pathology Queensland Central Laboratory, Australia; WHO Collaborating Centre for Gonorrhoea and other STIs, Sweden; G. Tonkin-Hill, A. van Tonder and members of the Thomson team for helpful discussions during analysis. M.A.B. and N.R.T. were supported by Wellcome funding to the Sanger Institute (#206194). M.M. was funded by the UKRI and NIHR (COV0335; MR/V027956/1, NIHR200125) and the EDCTP (RIA2018D-249). D.M.W. was funded by a Queensland Advancing Clinical Research Fellowship from the Queensland Government. D.A.W. was supported by an Investigator Grant (1174555) from the National Health and Medical Research Council of Australia. S.A.L. was funded by the National Institutes of Health (R01 AI42143 and R01 AI123196). This research was funded in whole, or in part, by the Wellcome Trust (#206194). For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author-accepted manuscript version arising from this submission.

Publisher Copyright:
© 2021, The Author(s).

Keywords

MOLECULAR CLOCK
R PACKAGE
SELECTION
YAWS
RECOMBINATION
VISUALIZATION
EPIDEMIOLOGY
ALGORITHM
SEQUENCE
STRAINS

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10.1038/s41564-021-01000-z

Cite this

Beale, M. A., Marks, M., Cole, M. J., Lee, M. K., Pitt, R., Ruis, C., Balla, E., Crucitti, T., Ewens, M., Fernández-Naval, C., Grankvist, A., Guiver, M., Kenyon, C. R., Khairullin, R., Kularatne, R., Arando, M., Molini, B. J., Obukhov, A., Page, E. E., ... Thomson, N. R. (2021). Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis. Nature Microbiology, 6(12), 1549-1560. https://doi.org/10.1038/s41564-021-01000-z

@article{0f808688541d4545b72f0f6259752014,

title = "Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis",

abstract = "Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum, has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum, we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p.pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides.Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.",

keywords = "MOLECULAR CLOCK, R PACKAGE, SELECTION, YAWS, RECOMBINATION, VISUALIZATION, EPIDEMIOLOGY, ALGORITHM, SEQUENCE, STRAINS",

author = "Beale, {Mathew A.} and Michael Marks and Cole, {Michelle J.} and Lee, {Min Kuang} and Rachel Pitt and Christopher Ruis and Eszter Balla and Tania Crucitti and Michael Ewens and Candela Fern{\'a}ndez-Naval and Anna Grankvist and Malcolm Guiver and Kenyon, {Chris R.} and Rafil Khairullin and Ranmini Kularatne and Maider Arando and Molini, {Barbara J.} and Andrey Obukhov and Page, {Emma E.} and Fruzsina Petrovay and Cornelis Rietmeijer and Dominic Rowley and Sandy Shokoples and Erasmus Smit and Sweeney, {Emma L.} and George Taiaroa and Vera, {Jaime H.} and Christine Wenner{\aa}s and Whiley, {David M.} and Williamson, {Deborah A.} and Gwenda Hughes and Prenilla Naidu and Magnus Unemo and Mel Krajden and Lukehart, {Sheila A.} and Morshed, {Muhammad G.} and Helen Fifer and Thomson, {Nicholas R.}",

note = "Funding Information: M.K. declares institutional funding from Roche, Hologic and Siemens, which is unrelated to this work. The remaining authors declare no competing interests. The funders had no input into the study design, interpretation or decision to submit for publication. Funding Information: We thank the sequencing team at the Wellcome Sanger Institute, and C. Puethe and the Pathogen Informatics team for computational support; additional technical staff involved in sample diagnostics, DNA extraction and sample retrieval in laboratories at Public Health England and NHS laboratories, UK; British Columbia CDC and Alberta Precision Laboratories, Canada; National Public Health Center, Budapest, Hungary; FRC Kazan Scientific Center, Tuva, Russia; National Institute for Communicable Diseases, Johannesburg, South Africa; Institute of Tropical Medicine, Antwerp, Belgium; Sahlgrenska University Hospital, Gothenburg, Sweden; Hospital Vall d{\textquoteright}Hebron, Barcelona, Spain; Midlands Regional Hospital Portlaoise, Ireland; Pathology Queensland Central Laboratory, Australia; WHO Collaborating Centre for Gonorrhoea and other STIs, Sweden; G. Tonkin-Hill, A. van Tonder and members of the Thomson team for helpful discussions during analysis. M.A.B. and N.R.T. were supported by Wellcome funding to the Sanger Institute (#206194). M.M. was funded by the UKRI and NIHR (COV0335; MR/V027956/1, NIHR200125) and the EDCTP (RIA2018D-249). D.M.W. was funded by a Queensland Advancing Clinical Research Fellowship from the Queensland Government. D.A.W. was supported by an Investigator Grant (1174555) from the National Health and Medical Research Council of Australia. S.A.L. was funded by the National Institutes of Health (R01 AI42143 and R01 AI123196). This research was funded in whole, or in part, by the Wellcome Trust (#206194). For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41564-021-01000-z",

language = "English",

volume = "6",

pages = "1549--1560",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature Research",

number = "12",

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Beale, MA, Marks, M, Cole, MJ, Lee, MK, Pitt, R, Ruis, C, Balla, E, Crucitti, T, Ewens, M, Fernández-Naval, C, Grankvist, A, Guiver, M, Kenyon, CR, Khairullin, R, Kularatne, R, Arando, M, Molini, BJ, Obukhov, A, Page, EE, Petrovay, F, Rietmeijer, C, Rowley, D, Shokoples, S, Smit, E, Sweeney, EL, Taiaroa, G, Vera, JH, Wennerås, C, Whiley, DM, Williamson, DA, Hughes, G, Naidu, P, Unemo, M, Krajden, M, Lukehart, SA, Morshed, MG, Fifer, H & Thomson, NR 2021, 'Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis', Nature Microbiology, vol. 6, no. 12, pp. 1549-1560. https://doi.org/10.1038/s41564-021-01000-z

TY - JOUR

T1 - Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis

AU - Beale, Mathew A.

AU - Marks, Michael

AU - Cole, Michelle J.

AU - Lee, Min Kuang

AU - Pitt, Rachel

AU - Ruis, Christopher

AU - Balla, Eszter

AU - Crucitti, Tania

AU - Ewens, Michael

AU - Fernández-Naval, Candela

AU - Grankvist, Anna

AU - Guiver, Malcolm

AU - Kenyon, Chris R.

AU - Khairullin, Rafil

AU - Kularatne, Ranmini

AU - Arando, Maider

AU - Molini, Barbara J.

AU - Obukhov, Andrey

AU - Page, Emma E.

AU - Petrovay, Fruzsina

AU - Rietmeijer, Cornelis

AU - Rowley, Dominic

AU - Shokoples, Sandy

AU - Smit, Erasmus

AU - Sweeney, Emma L.

AU - Taiaroa, George

AU - Vera, Jaime H.

AU - Wennerås, Christine

AU - Whiley, David M.

AU - Williamson, Deborah A.

AU - Hughes, Gwenda

AU - Naidu, Prenilla

AU - Unemo, Magnus

AU - Krajden, Mel

AU - Lukehart, Sheila A.

AU - Morshed, Muhammad G.

AU - Fifer, Helen

AU - Thomson, Nicholas R.

N1 - Funding Information: M.K. declares institutional funding from Roche, Hologic and Siemens, which is unrelated to this work. The remaining authors declare no competing interests. The funders had no input into the study design, interpretation or decision to submit for publication. Funding Information: We thank the sequencing team at the Wellcome Sanger Institute, and C. Puethe and the Pathogen Informatics team for computational support; additional technical staff involved in sample diagnostics, DNA extraction and sample retrieval in laboratories at Public Health England and NHS laboratories, UK; British Columbia CDC and Alberta Precision Laboratories, Canada; National Public Health Center, Budapest, Hungary; FRC Kazan Scientific Center, Tuva, Russia; National Institute for Communicable Diseases, Johannesburg, South Africa; Institute of Tropical Medicine, Antwerp, Belgium; Sahlgrenska University Hospital, Gothenburg, Sweden; Hospital Vall d’Hebron, Barcelona, Spain; Midlands Regional Hospital Portlaoise, Ireland; Pathology Queensland Central Laboratory, Australia; WHO Collaborating Centre for Gonorrhoea and other STIs, Sweden; G. Tonkin-Hill, A. van Tonder and members of the Thomson team for helpful discussions during analysis. M.A.B. and N.R.T. were supported by Wellcome funding to the Sanger Institute (#206194). M.M. was funded by the UKRI and NIHR (COV0335; MR/V027956/1, NIHR200125) and the EDCTP (RIA2018D-249). D.M.W. was funded by a Queensland Advancing Clinical Research Fellowship from the Queensland Government. D.A.W. was supported by an Investigator Grant (1174555) from the National Health and Medical Research Council of Australia. S.A.L. was funded by the National Institutes of Health (R01 AI42143 and R01 AI123196). This research was funded in whole, or in part, by the Wellcome Trust (#206194). For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author-accepted manuscript version arising from this submission. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum, has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum, we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p.pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides.Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.

AB - Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum, has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum, we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p.pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides.Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.

KW - MOLECULAR CLOCK

KW - R PACKAGE

KW - SELECTION

KW - YAWS

KW - RECOMBINATION

KW - VISUALIZATION

KW - EPIDEMIOLOGY

KW - ALGORITHM

KW - SEQUENCE

KW - STRAINS

UR - http://www.scopus.com/inward/record.url?scp=85119854843&partnerID=8YFLogxK

U2 - 10.1038/s41564-021-01000-z

DO - 10.1038/s41564-021-01000-z

M3 - Article

AN - SCOPUS:85119854843

SN - 2058-5276

VL - 6

SP - 1549

EP - 1560

JO - Nature Microbiology

JF - Nature Microbiology

IS - 12

ER -

Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis

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Keywords

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