Transcriptional and immunological analysis of the putative outer membrane protein and vaccine candidate TprL of Treponema pallidum

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Abstract
Background: An effective syphilis vaccine should elicit antibodies toTreponema pallidumsubsp.pallidum(T.p.pallidum) surface antigens to induce pathogen clearance through opsonophagocytosis. Although the combination of bioinformatics, structural, and functional analyses ofT.p.pallidumgenes 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 thattp1031, theT.p.pallidumgene encoding the putative OMP and vaccine candidate TprL is differentially expressed in severalT.p.pallidumstrains, suggesting transcriptional regulation. Experimental identification of thetprLtranscriptional start site revealed that a homopolymeric G sequence of varying length resides within thetprLpromoter and that its length affects promoter activity compatible with phase variation. Conversely, in the closely related pathogenT.p. subsp.pertenue, the agent of yaws, where a naturally-occurring deletion has eliminated thetprLpromoter region, elements necessary for protein synthesis, and part of the gene ORF,tprLtranscription level are negligible compared toT.p.pallidumstrains. Accordingly, the humoral response to TprL is absent in yaws-infected laboratory animals and patients compared to syphilis-infected subjects.Conclusion: The ability ofT.p.pallidumto stochastically varytprLexpression should be considered in any vaccine development effort that includes this antigen. The role of phase variation in contributing toT.p.pallidumantigenic diversity should be further studied.
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Funding Information
  • National Institute of Allergy and Infectious Diseases (R01AI139265)
  • National Institute of Allergy and Infectious Diseases (U19AI144133)

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