Treponema pallidum subsp. pallidum (TPA) is an obligatory human pathogen causing syphilis. Despite the existence of numerous virulence factor predictions and preliminary findings, there are no experimentally identified and no experimentally proven TPA virulence factors. Within this proposal, we are planning to experimentally identify TPA virulence factors. For the purpose of this grant proposal, the genes encoding virulence factors will be defined as those highly expressed in the samples directly taken from infected patients, genes that can be deleted from the TPA strains grown under in vitro conditions and genes which deletion results in mutant TPA strains with unchanged or accelerated growth rate in in vitro. To identify genes highly transcribed in in vivo, transcriptome analyses of TPA present in human clinical samples and in isogenic TPA cultures grown under in vitro conditions will be performed. Subsequently, the identified gene candidates will be used to construct a set of mutant TPA strains with deleted/inactivated genes of interest and each individual mutant strain will be compared to in vitro grown parental strains. The mutant TPA strains with unchanged or accelerated growth rate under in vitro conditions will be selected and further tested for their in vitro characteristics including interaction with eukaryotic cells. The identified TPA virulence factors could serve as potential targets to develop new therapeutics and/or vaccine against syphilis.

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