Genome sequencing of 196 Treponema pallidum strains from six continents reveals additional variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar
Greninger Alexander L. 1Lieberman Nicole A.P. 2Shrestha Lasata 2Huang Meei-Li 2Haynes Austin M. 3Wang Qian-Qiu 4Kou Cai-Xia 4Ciccarese Giulia 5Nakayama Shu-ichi 6Lee Kenichi 6Ohnishi Makoto 6Mitj¨¤ Oriol 7Rompalo Anne 8Casto Amanda M. 9Giacani Lorenzo 10Lin Michelle J. 2Eguiluz Maria 11Romeis Emily 3Drago Francesco 5Vargas Silver K. 11Nguyen Tien 2Roychoudhury Pavitra 1Lukehart Sheila A. 10Caceres Carlos F. 11Mulcahy Fiona 12Xie Hong 2DiMaio Frank 13Konda Kelika A. 14Klausner Jeffrey D. 15Hook Edward W. 16Dal Conte Ivano 17Zhang Rui-Li 18Cusini Marco19
作者信息
- 1. Department of Laboratory Medicine and Pathology, University of Washington||Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
- 2. Department of Laboratory Medicine and Pathology, University of Washington
- 3. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington
- 4. Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College||National Center for STD Control, China Centers for Disease Control and Prevention
- 5. Health Sciences Department, Section of Dermatology, San Martino University Hospital
- 6. Department of Bacteriology I, National Institute of Infectious Diseases
- 7. Fight Aids and Infectious Diseases Foundation, Hospital Germans Trias i Pujol||Lihir Medical Centre-International SOS
- 8. Department of Infectious Diseases, Johns Hopkins Medical Institutions
- 9. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington||Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
- 10. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington||Department of Global Health, University of Washington
- 11. Unit of Health, Sexuality and Human Development and Laboratory of Sexual Health, Universidad Peruana Cayetano-Heredia
- 12. Department of Genito Urinary Medicine and Infectious Diseases, St James?ˉs Hospital
- 13. Department of Biochemistry, University of Washington
- 14. Unit of Health, Sexuality and Human Development and Laboratory of Sexual Health, Universidad Peruana Cayetano-Heredia||Keck School of Medicine, University of Southern California
- 15. Keck School of Medicine, University of Southern California
- 16. Department of Medicine, University of Alabama
- 17. STI Clinic, Infectious Diseases Unit, University of Turin
- 18. Department of Dermatology, The Second Affiliated Hospital of Nanjing Medical University
- 19. Fondazione IRCCS Ca?ˉ Granda, Ospedale Maggiore Policlinico
- 折叠
Abstract
Abstract
In spite of its immutable susceptibility to penicillin, Treponema pallidum (T. pallidum) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T. pallidum strains – including 191 T. pallidum subsp. pallidum – sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T. pallidum subsp. pallidum and subsp. endemicum, shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543-1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens.
Author SummaryEach year, millions of new cases of venereal and congenital syphilis, caused by the bacterium Treponema pallidum (T. pallidum) subsp. pallidum, are diagnosed worldwide, resulting in significant morbidity and mortality. Alongside endemic circulation of syphilis in low-income countries, disease resurgence in high-income nations has underscored the need for a vaccine. Due to prior technological limitations in culturing and sequencing the organism, the extent of the genetic diversity within modern strains of T. pallidum subsp. pallidum remains poorly understood, hampering development of a broadly protective vaccine. In this study, we obtained 196 near-complete T. pallidum genomes directly from clinical swabs from eight countries across six continents. Of these, 191 were identified as T. pallidum subsp. pallidum, including 90 Nichols clade genomes. Bayesian analysis revealed a high degree of variance in mutation rate among subclades. Interestingly, a Nichols subclade with a particularly high mutation rate harbors a non-synonymous mutation in a putative DNA repair helicase. Coupling sequencing data with protein structure prediction, we identified multiple novel amino acid variants in several proteins previously identified as potential vaccine candidates. Our data help inform current efforts to develop a broadly protective syphilis vaccine.引用本文复制引用
Greninger Alexander L.,Lieberman Nicole A.P.,Shrestha Lasata,Huang Meei-Li,Haynes Austin M.,Wang Qian-Qiu,Kou Cai-Xia,Ciccarese Giulia,Nakayama Shu-ichi,Lee Kenichi,Ohnishi Makoto,Mitj¨¤ Oriol,Rompalo Anne,Casto Amanda M.,Giacani Lorenzo,Lin Michelle J.,Eguiluz Maria,Romeis Emily,Drago Francesco,Vargas Silver K.,Nguyen Tien,Roychoudhury Pavitra,Lukehart Sheila A.,Caceres Carlos F.,Mulcahy Fiona,Xie Hong,DiMaio Frank,Konda Kelika A.,Klausner Jeffrey D.,Hook Edward W.,Dal Conte Ivano,Zhang Rui-Li,Cusini Marco.Genome sequencing of 196 Treponema pallidum strains from six continents reveals additional variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar[EB/OL].(2025-03-28)[2026-04-03].https://www.biorxiv.org/content/10.1101/2021.08.17.456619.学科分类
皮肤病学、性病学/微生物学/基础医学
评论