Estimation of Full-Length TprK Diversity in Treponema pallidum subsp. .

Immune evasion and disease progression of subsp. are associated with sequence diversity in the hypervariable outer membrane protein TprK. Previous attempts to study variation within TprK have sequenced at depths insufficient to fully appreciate the hypervariable nature of the protein, failed to establish linkage between the protein's seven variable regions, or were conducted on isolates passed through rabbits. As a consequence, a complete profile of during infection in the human host is still lacking. Furthermore, prior studies examining how subsp. uses its repertoire of genomic donor sites to generate diversity within the variable regions of the have yielded a partial understanding of this process due to the limited number of alleles examined. In this study, we used short- and long-read deep sequencing to directly characterize full-length alleles from subsp. collected from early lesions of patients attending two sexually transmitted infection clinics in Italy. We demonstrate that strains collected from cases of secondary syphilis contain significantly more unique variable region sequences and full-length TprK sequences than those from cases of primary syphilis. Our data, combined with recent data available on Chinese subsp. specimens, show the near-complete absence of overlap in TprK sequences among the 41 specimens profiled to date. We further estimate that the potential antigenic variability carried by TprK rivals that of current estimates of the human adaptive immune system. These data underscore the immunoevasive ability of TprK that allows subsp. to establish lifelong infection. Syphilis continues to be a significant public health issue in both low- and high-income countries, including the United States where the rate of syphilis infection has increased over the past 5 years. subsp. , the causative agent of syphilis, carries the outer membrane protein TprK that undergoes segmental gene conversion to constantly create new sequences. We performed full-length deep sequencing of TprK to examine TprK diversity in clinical subsp. strains. We then combined our results with data from all samples for which TprK deep sequencing results were available. We found almost no overlap in TprK sequences between different patients. Moreover, our data allowed us to estimate the total number of TprK variants that subsp. can potentially generate. Our results support how the subsp. TprK antigenic variation system is an equal adversary of the human immune system leading to pathogen persistence in the host.