Austin M Haynes1, Mark Fernandez2, Emily Romeis1, Oriol Mitjà3,4, Kelika A Konda5,6, Silver K Vargas5,7, Maria Eguiluz5, Carlos F Caceres5, Jeffrey D Klausner6, Lorenzo Giacani1,2. 1. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, United States of America. 2. Department of Global Health, University of Washington, Seattle, Washington, United States of America. 3. Fight Aids and Infectious Diseases Foundation, Hospital Germans Trias I Pujol, Badalona, Barcelona, Spain. 4. Lihir Medical Centre-International SOS, Newcrest Mining, Lihir Island, Papua New Guinea. 5. Unit of Health, Sexuality and Human Development and Laboratory of Sexual Health, Universidad Peruana Cayetano-Heredia, Lima, Peru. 6. David Geffen School of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, United States of America. 7. School of Public Health and Administration "Carlos Vidal Layseca", Universidad Peruana Cayetano-Heredia, Lima, Peru.
Abstract
BACKGROUND: An effective syphilis vaccine should elicit antibodies to Treponema pallidum subsp. pallidum (T. p. pallidum) surface antigens to induce pathogen clearance through opsonophagocytosis. Although the combination of bioinformatics, structural, and functional analyses of T. p. pallidum genes to identify putative outer membrane proteins (OMPs) resulted in a list of potential vaccine candidates, still very little is known about whether and how transcription of these genes is regulated during infection. This knowledge gap is a limitation to vaccine design, as immunity generated to an antigen that can be down-regulated or even silenced at the transcriptional level without affecting virulence would not induce clearance of the pathogen, hence allowing disease progression. PRINCIPAL FINDINGS: We report here that tp1031, the T. p. pallidum gene encoding the putative OMP and vaccine candidate TprL is differentially expressed in several T. p. pallidum strains, suggesting transcriptional regulation. Experimental identification of the tprL transcriptional start site revealed that a homopolymeric G sequence of varying length resides within the tprL promoter and that its length affects promoter activity compatible with phase variation. Conversely, in the closely related pathogen T. p. subsp. pertenue, the agent of yaws, where a naturally-occurring deletion has eliminated the tprL promoter region, elements necessary for protein synthesis, and part of the gene ORF, tprL transcription level are negligible compared to T. p. pallidum strains. Accordingly, the humoral response to TprL is absent in yaws-infected laboratory animals and patients compared to syphilis-infected subjects. CONCLUSION: The ability of T. p. pallidum to stochastically vary tprL expression should be considered in any vaccine development effort that includes this antigen. The role of phase variation in contributing to T. p. pallidum antigenic diversity should be further studied.
BACKGROUND: An effective syphilis vaccine should elicit antibodies to Treponema pallidum subsp. pallidum (T. p. pallidum) surface antigens to induce pathogen clearance through opsonophagocytosis. Although the combination of bioinformatics, structural, and functional analyses of T. p. pallidum genes to identify putative outer membrane proteins (OMPs) resulted in a list of potential vaccine candidates, still very little is known about whether and how transcription of these genes is regulated during infection. This knowledge gap is a limitation to vaccine design, as immunity generated to an antigen that can be down-regulated or even silenced at the transcriptional level without affecting virulence would not induce clearance of the pathogen, hence allowing disease progression. PRINCIPAL FINDINGS: We report here that tp1031, the T. p. pallidum gene encoding the putative OMP and vaccine candidate TprL is differentially expressed in several T. p. pallidum strains, suggesting transcriptional regulation. Experimental identification of the tprL transcriptional start site revealed that a homopolymeric G sequence of varying length resides within the tprL promoter and that its length affects promoter activity compatible with phase variation. Conversely, in the closely related pathogen T. p. subsp. pertenue, the agent of yaws, where a naturally-occurring deletion has eliminated the tprL promoter region, elements necessary for protein synthesis, and part of the gene ORF, tprL transcription level are negligible compared to T. p. pallidum strains. Accordingly, the humoral response to TprL is absent in yaws-infected laboratory animals and patients compared to syphilis-infected subjects. CONCLUSION: The ability of T. p. pallidum to stochastically vary tprL expression should be considered in any vaccine development effort that includes this antigen. The role of phase variation in contributing to T. p. pallidum antigenic diversity should be further studied.
Authors: David L Cox; Amit Luthra; Star Dunham-Ems; Daniel C Desrosiers; Juan C Salazar; Melissa J Caimano; Justin D Radolf Journal: Infect Immun Date: 2010-09-27 Impact factor: 3.441
Authors: Lorenzo Giacani; Barbara J Molini; Eric Y Kim; B Charmie Godornes; B Troy Leader; Lauren C Tantalo; Arturo Centurion-Lara; Sheila A Lukehart Journal: J Immunol Date: 2010-02-26 Impact factor: 5.422
Authors: C M Fraser; S J Norris; G M Weinstock; O White; G G Sutton; R Dodson; M Gwinn; E K Hickey; R Clayton; K A Ketchum; E Sodergren; J M Hardham; M P McLeod; S Salzberg; J Peterson; H Khalak; D Richardson; J K Howell; M Chidambaram; T Utterback; L McDonald; P Artiach; C Bowman; M D Cotton; C Fujii; S Garland; B Hatch; K Horst; K Roberts; M Sandusky; J Weidman; H O Smith; J C Venter Journal: Science Date: 1998-07-17 Impact factor: 47.728
Authors: Nicole A P Lieberman; Michelle J Lin; Hong Xie; Lasata Shrestha; Tien Nguyen; Meei-Li Huang; Austin M Haynes; Emily Romeis; Qian-Qiu Wang; Rui-Li Zhang; Cai-Xia Kou; Giulia Ciccarese; Ivano Dal Conte; Marco Cusini; Francesco Drago; Shu-Ichi Nakayama; Kenichi Lee; Makoto Ohnishi; Kelika A Konda; Silver K Vargas; Maria Eguiluz; Carlos F Caceres; Jeffrey D Klausner; Oriol Mitjà; Anne Rompalo; Fiona Mulcahy; Edward W Hook; Sheila A Lukehart; Amanda M Casto; Pavitra Roychoudhury; Frank DiMaio; Lorenzo Giacani; Alexander L Greninger Journal: PLoS Negl Trop Dis Date: 2021-12-22