Treponema pallidum subsp. pallidum is the causative agent of syphilis, a sexually transmitted disease with worldwide prevalence. Several different molecular typing schemes are currently available for this pathogen. To enable population biology studies of the syphilis agent and for epidemiological surveillance at the global scale, a harmonized typing tool needs to be introduced. Recently, we published a new multi-locus sequence typing (MLST) with the potential to significantly enhance the epidemiological data in several aspects (e.g., distinguishing genetically different clades of syphilis, subtyping inside these clades, and finally, distinguishing different subspecies of non-cultivable pathogenic treponemes). In this short report, we introduce the PubMLST database for treponemal DNA data storage and for assignments of allelic profiles and sequencing types. Moreover, we have summarized epidemiological data of all treponemal strains (n = 358) with available DNA sequences in typing loci and found several association between genetic groups and characteristics of patients. This study proposes the establishment of a single MLST of T. p. pallidum and encourages researchers and public health communities to use this PubMLST database as a universal tool for molecular typing studies of the syphilis pathogen.

Biology of Spirochetes Unit Institut Pasteur Paris France

Department of Biology Masaryk University Brno Czech Republic

Department of Zoology University of Oxford Oxford UK

Zobrazit více v PubMed

Argimón S, Abudahab K, Goater RJE, Fedosejev A, Bhai J, Glasner C, Feil EJ, Holden MTG, Yeats CA, Grundmann H, Spratt BG, Aanensen DM. Microreact: visualizing and sharing data for genomic epidemiology and phylogeography. Microbial Genomics. 2016;2:e000093. doi: 10.1099/mgen.0.000093. PubMed DOI PMC

Arora N, Schuenemann VJ, Jäger G, Peltzer A, Seitz A, Herbig A, Strouhal M, Grillová L, Sánchez-Busó L, Kühnert D, Bos KI, Davis LR, Mikalová L, Bruisten S, Komericki P, French P, Grant PR, Pando MA, Vaulet LG, Fermepin MR, Martinez A, Centurion Lara A, Giacani L, Norris SJ, Šmajs D, Bosshard PP, González-Candelas F, Nieselt K, Krause J, Bagheri HC. Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster. Nature Microbiology. 2016;2:16245. doi: 10.1038/nmicrobiol.2016.245. PubMed DOI

Edmondson DG, Hu B, Norris SJ. Long-term in vitro culture of the syphilis spirochete Treponema pallidum subsp. pallidum. American Society for Microbiology. 2018;9:e011153-18. doi: 10.1128/mBio.01153-18. PubMed DOI PMC

Gallo Vaulet L, Grillová L, Mikalová L, Casco R, Rodríguez Fermepin M, Pando MA, Šmajs D. Molecular typing of Treponema pallidum isolates from Buenos Aires, Argentina: frequent Nichols-like isolates and low levels of macrolide resistance. PLOS ONE. 2017;12(2):e0172905. doi: 10.1371/journal.pone.0172905. PubMed DOI PMC

Giacani L, Iverson-Cabral SL, King JCK, Molini BJ, Lukehart SA, Centurion-Lara A. Complete genome sequence of the Treponema pallidum subsp. pallidum Sea81-4 Strain. Genome Announcements. 2014;2(2):e00333-14. doi: 10.1128/genomeA.00333-14. PubMed DOI PMC

Giacani L, Jeffrey BM, Molini BJ, Le HT, Lukehart SA, Centurion-Lara A, Rockey DD. Complete genome sequence and annotation of the Treponema pallidum subsp. pallidum Chicago strain. Journal of Bacteriology. 2010;192:2645–2646. doi: 10.1128/JB.00159-10. PubMed DOI PMC

Grange PA, Mikalová L, Gaudin C, Strouhal M, Janier M, Benhaddou N, Šmajs D, Dupin N. Treponema pallidum 11qj subtype may correspond to a Treponema pallidum subsp. Endemicum strain. Sexually Transmitted Diseases. 2016;43(8):517–518. doi: 10.1097/OLQ.0000000000000474. PubMed DOI

Grillová L, Bawa T, Mikalová L, Gayet-Ageron A, Nieselt K, Strouhal M, Sednaoui P, Ferry T, Cavassini M, Lautenschlager S, Dutly F, Pla-Díaz M, Krützen M, González-Candelas F, Bagheri HC, Šmajs D, Arora N, Bosshard PP. Molecular characterization of Treponema pallidum subsp. pallidum in Switzerland and France with a new multilocus sequence typing scheme. PLOS ONE. 2018a;13(7):e0200773. doi: 10.1371/journal.pone.0200773. PubMed DOI PMC

Grillová L, Giacani L, Mikalová L, Strouhal M, Strnadel R, Marra C, Centurion-Lara A, Poveda L, Russo G, Čejková D, Vašků V, Oppelt J, Šmajs D. Sequencing of Treponema pallidum subsp. pallidum from isolate UZ1974 using anti-treponemal antibodies enrichment: first complete whole genome sequence obtained directly from human clinical material. PLOS ONE. 2018b;3(8):e0202619. doi: 10.1371/journal.pone.0202619. PubMed DOI PMC

Grillová L, Pětrošová H, Mikalová L, Strnadel R, Dastychová E, Kuklová I, Kojanová M, Kreidlová M, Vaňousová D, Hercogová J, Procházka P, Zákoucká H, Krchňáková A, Vašků V, Šmajs D. Molecular typing of Treponema pallidum subsp. pallidum in the Czech Republic during 2011 to 2013: increased prevalence of identified genotypes and of isolates with macrolide resistance. Journal of Clinical Microbiology. 2014;52(10):3693–37000. doi: 10.1128/jcm.01292-14. PubMed DOI PMC

Jolley KA, Bray JE, Maiden MCJ. Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications [version 1; referees: awaiting peer review] Wellcome Open Research. 2018;3:124. doi: 10.12688/wellcomeopenres.14826.1. PubMed DOI PMC

Jolley KA, Maiden MCJ. BIGSdb: scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics. 2010;11:595. doi: 10.1186/1471-2105-11-595. PubMed DOI PMC

Letunic I, Bork P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Research. 2016;44(W1):W242–W245. doi: 10.1093/nar/gkw290. PubMed DOI PMC

Maiden MCJ, Jansen van Rensburg MJ, Bray JE, Earle SG, Ford SA, Jolley KA, McCarthy ND. MLST revisited: the gene-by-gene approach to bacterial genomics. Nature Reviews Microbiology. 2013;11:728–736. doi: 10.1038/nrmicro3093. PubMed DOI PMC

Marra CM, Sahi SK, Tantalo LC, Godornes C, Reid T, Behets F, Rompalo A, Klausner JD, Yin YP, Mulcahy F, Golden MR, Centurion-Lara A, Lukehart SA. Enhanced molecular typing of Treponema pallidum: geographical distribution of strain types and association with neurosyphilis. Journal of Infectious Diseases. 2010;202(9):1380–1388. doi: 10.1086/656533. PubMed DOI PMC

Mikalová L, Pospíšilová P, Woznicová V, Kuklová I, Zákoucká H, Šmajs D. Comparison of CDC and sequence-based molecular typing of syphilis treponemes: tpr and arp loci are variable in multiple samples from the same patient. BMC Microbiology. 2013;13:178. doi: 10.1186/1471-2180-13-178. PubMed DOI PMC

Nechvátal L, Pětrošová H, Grillová L, Pospíšilová P, Mikalová L, Strnadel R, Kuklová I, Kojanová M, Kreidlová M, Vaňousová D, Procházka P, Zákoucká H, Krchňáková A, Šmajs D. Syphilis-causing strains belong to separate SS14-like or Nichols-like groups as defined by multilocus analysis of 19 Treponema pallidum strains. International Journal of Medical Microbiology. 2014;304(5–6):645–653. doi: 10.1016/j.ijmm.2014.04.007. PubMed DOI

Noda AA, Grillová L, Lienhard R, Blanco O, Rodríguez I, Šmajs D. Bejel in Cuba: molecular identification of Treponema pallidum subsp. endemicum in patients diagnosed with venereal syphilis. Clinical Microbiology and Infection. 2018;24(11):1210.e1–1210.e5. doi: 10.1016/j.cmi.2018.02.006. PubMed DOI

Peng R-R, Wang AL, Li J, Tucker JD, Yin Y-P, Chen X-S. Molecular typing of Treponema pallidum: a systematic review and meta-analysis. PLOS Neglected Tropical Diseases. 2011;5(11):e1273. doi: 10.1371/journal.pntd.0001273. PubMed DOI PMC

Pětrošová H, Pospíšilová P, Strouhal M, Čejková D, Zobaníková M, Mikalová L, Sodergren E, Weinstock GM, Šmajs D. Resequencing of Treponema pallidum ssp. pallidum strains Nichols and SS14: correction of sequencing errors resulted in increased separation of syphilis treponeme subclusters. PLOS ONE. 2013;8(9):e74319. doi: 10.1371/journal.pone.0074319. PubMed DOI PMC

Pětrošová H, Zobaníková M, Čejková D, Mikalová L, Pospíšilová P, Strouhal M, Chen L, Qin X, Muzny DM, Weinstock GM, Šmajs D. Whole genome sequence of Treponema pallidum ssp. pallidum, strain Mexico A, suggests recombination between yaws and syphilis strains. PLOS Neglected Tropical Diseases. 2012;6(9):e1832. doi: 10.1371/journal.pntd.0001832. PubMed DOI PMC

Pinto M, Antelo M, Ferreira R, Azevedo J, Santo I, Borrego MJ, Gomes JP. A retrospective cross-sectional quantitative molecular approach in biological samples from patients with syphilis. Microbial Pathogenesis. 2017;104:296–302. doi: 10.1016/j.micpath.2017.01.059. PubMed DOI

Pinto M, Borges V, Antelo M, Pinheiro M, Nunes A, Azevedo J, Borrego MJ, Mendonça J, Carpinteiro D, Vieira L, Gomes JP. Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation. Nature Microbiology. 2016;2(1):16190. doi: 10.1038/nmicrobiol.2016.190. PubMed DOI

Pospíšilová P, Grange PA, Grillová L, Mikalová L, Martinet P, Janier M, Vermersch A, Benhaddou N, Del Giudice P, Alcaraz I, Truchetet F, Dupin N, Šmajs D. Multi-locus sequence typing of Treponema pallidum subsp. pallidum present in clinical samples from France: infecting treponemes are genetically diverse and belong to 18 allelic profiles. PLOS ONE. 2018;13(7):e0201068. doi: 10.1371/journal.pone.0201068. PubMed DOI PMC

Radolf JD, Deka RK, Anand A, Šmajs D, Norgard MV, Yang XF. Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen. Nature Reviews Microbiology. 2016;14(12):744–759. doi: 10.1038/nrmicro.2016.141. PubMed DOI PMC

Read P, Tagg KA, Jeoffreys N, Guy RJ, Gilbert GL, Donovan B. Treponema pallidum strain types and association with macrolide resistance in Sydney, Australia: New TP0548 gene types identified. Journal of Clinical Microbiology. 2016;54(8):2172–2174. doi: 10.1128/JCM.00959-16. PubMed DOI PMC

Šmajs D, Mikalova L, Strouhal M, Grillova L. Why are there two genetically distinct syphilis-causing strains? Forum on Immunopathological Diseases and Therapeutics. 2016;7:181–190. doi: 10.1615/ForumImmunDisTher.2017020184. DOI

Šmajs D, Norris SJ, Weinstock GM. Genetic diversity in Treponema pallidum: implications for pathogenesis, evolution and molecular diagnostics of syphilis and yaws. Infection, Genetics and Evolution. 2012;12(2):191–202. doi: 10.1016/j.meegid.2011.12.001. PubMed DOI PMC

Šmajs D, Strouhal M, Knauf S. Genetics of human and animal uncultivable treponemal pathogens. Infection, Genetics and Evolution. 2018;61:92–107. doi: 10.1016/j.meegid.2018.03.015. PubMed DOI

Strouhal M, Oppelt J, Mikalová L, Arora N, Nieselt K, González-Candelas F, Šmajs D. Reanalysis of Chinese Treponema pallidum samples: all Chinese samples cluster with SS14-like group of syphilis-causing treponemes. BMC Research Notes. 2018;11:16. doi: 10.1186/s13104-017-3106-7. PubMed DOI PMC

Sun J, Meng Z, Wu K, Liu B, Zhang S, Liu Y, Wang Y, Zheng H, Huang J, Zhou P. Tracing the origin of Treponema pallidum in China using next-generation sequencing. Oncotarget. 2016;7:42904–42918. doi: 10.18632/oncotarget.10154. PubMed DOI PMC

Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: molecular evolutionary genetics analysis version 6.0. Molecular Biology and Evolution. 2013;30(12):2725–2729. doi: 10.1093/molbev/mst197. PubMed DOI PMC

Tong M-L, Zhao Q, Liu L-L, Zhu X-Z, Gao K, Zhang H-L, Lin L-R, Niu J-J, Ji Z-L, Yang T-C. Whole genome sequence of the Treponema pallidum subsp. pallidum strain Amoy: an Asian isolate highly similar to SS14. PLOS ONE. 2017;12:e0182768. doi: 10.1371/journal.pone.0182768. PubMed DOI PMC

World Health Organization WHO guidelines for the treatment of Treponema pallidum (syphilis) 2016. http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ PubMed

Zhou Z, Alikhan N-F, Sergeant MJ, Luhmann N, Vaz C, Francisco AP, Carriço JA, Achtman M. GrapeTree: visualization of core genomic relationships among 100,000 bacterial pathogens. Genome Research. 2018;28(9):1395–1404. doi: 10.1101/gr.232397.117. PubMed DOI PMC

Zobaníková M, Mikolka P, Cejková D, Pospíšilová P, Chen L, Strouhal M, Qin X, Weinstock GM, Šmajs D. Complete genome sequence of Treponema pallidum strain DAL-1. Standards in Genomic Sciences. 2012;7(1):12–21. doi: 10.4056/sigs.2615838. PubMed DOI PMC

Analysis of Treponema pallidum subsp. pallidum predicted outer membrane proteins (OMPeomes) in 21 clinical samples: variant sequences are predominantly surface-exposed

In vitro analysis of seven syphilis-causing Treponema pallidum strains revealed inherent growth rate differences

A new typing scheme demonstrates high discriminatory power for Treponema pallidum subspecies

Resistance to ceftriaxone and penicillin G among contemporary syphilis strains confirmed by natural in vitro mutagenesis

Majority of Treponema pallidum ssp. pallidum MLST allelic profiles in the Czech Republic (2004-2022) belong to two SS14-like clusters

High prevalence and genetic diversity of Treponema paraluisleporidarum isolates in European lagomorphs

High frequency of Nichols-like strains and increased levels of macrolide resistance in Treponema pallidum in clinical samples from Buenos Aires, Argentina

No bejel among Surinamese, Antillean and Dutch syphilis diagnosed patients in Amsterdam between 2006-2018 evidenced by multi-locus sequence typing of Treponema pallidum isolates

Directly Sequenced Genomes of Contemporary Strains of Syphilis Reveal Recombination-Driven Diversity in Genes Encoding Predicted Surface-Exposed Antigens

MLST typing of Treponema pallidum subsp. pallidum in the Czech Republic during 2004-2017: Clinical isolates belonged to 25 allelic profiles and harbored 8 novel allelic variants