Subfamily I Treponema pallidum repeat proteins: Sequence variation and immunity

A twelve-membered Treponema pallidum repeat (Tpr) protein family has been identified in T. pallidum subsp. pallidum, the causative agent of syphilis. The subfamily I Tpr proteins (C, D, F, and I) possess conserved sequence at the N- and C-termini and unique central regions differentiating each member. These proteins may be important in understanding the immune response during syphilis infection and protective immunity. These proteins all have a predicted cleavable N-terminal signal sequence, suggesting possible outer membrane localization. Some variation has been identified in subfamily I (TprD/D2) among T. pallidum subsp. pallidum isolates. In this dissertation, we wished to determine the degree of heterogeneity of the remaining subfamily I tpr sequences. While some heterogeneity was identified in TprC among T. pallidum subsp. pallidum isolates, TprF and TprI were conserved. Strong antibody responses have also been observed toward some subfamily I Tpr recombinant proteins during infection with different syphilis isolates. As a considerable portion of the subfamily I Tpr proteins comprise of conserved sequence, we examined the immune response during experimental syphilis to the N-terminal and C-terminal conserved regions of the subfamily I Tpr proteins. Preliminary data also suggested that immunization with the whole TprF protein attenuates lesion development following homologous intradermal challenge. We further investigated the protective capacity of the whole TprF recombinant protein, as well as the N-terminal conserved portion and the TprF nonconserved central region, against infectious challenge in this dissertation. In these studies, we have demonstrated that the N-terminal conserved region of subfamily I Tpr proteins elicits strong antibody and T-cell responses during infection with different infectious strains. Immunization with this conserved peptide also attenuates syphilitic lesion development upon infectious challenge with two different strains, and early clearance appears to be associated with delayed type hypersensitivity responses to the T-cell epitopes within the N-terminal conserved region. Given the high degree of conservation of the N-terminal conserved region among multiple isolates, it may be useful as a component in a broadly protective vaccine. The observation that infection still occurred in immunized rabbits suggests that immunization with additional antigens is necessary to obtain complete protection.