Directly Sequenced Genomes of Contemporary Strains of Syphilis Reveal Recombination-Driven Diversity in Genes Encoding Predicted Surface-Exposed Antigens

Abstract

Syphilis, caused by Treponema pallidum subsp. pallidum (TPA), remains an important public health problem with an increasing worldwide prevalence. Despite recent advances in in vitro cultivation, genetic variability of this pathogen during infection is poorly understood. Here, we present contemporary and geographically diverse complete treponemal genome sequences isolated directly from patients using a methyl-directed enrichment prior to sequencing. This approach reveals that approximately 50% of the genetic diversity found in TPA is driven by inter- and/or intra-strain recombination events, particularly in strains belonging to one of the defined genetic groups of syphilis treponemes: Nichols-like strains. Recombinant loci were found to encode putative outer-membrane proteins and the recombination variability was almost exclusively found in regions predicted to be at the host-pathogen interface. Genetic recombination has been considered to be a rare event in treponemes, yet our study unexpectedly showed that it occurs at a significant level and may have important impacts in the biology of this pathogen, especially as these events occur primarily in the outer membrane proteins. This study reveals the existence of strains with different repertoires of surface-exposed antigens circulating in the current human population, which should be taken into account during syphilis vaccine development.

Comparative genomics and full-length Tprk profiling of Treponema pallidum subsp. pallidum reinfection

“…Of those, 14 resulted in coding changes in 13 genes. Notably, all of the coding changes found in the reinfecting strain were identified in previously sequenced strains [13,21,32] and thus, likely reflect the diversity in the circulating T. pallidum population rather than selection from the host's immune response.…”

Phylogenetic and genetic characterization of Treponema pallidum strains from syphilis patients in Japan by whole-genome sequence analysis from global perspectives

“…These have identified some epidemiological features related to the subtype and to the prevalence of macrolide resistance in strains in different countries 6 . Although whole-genome sequence (WGS) analyses have provided phylogenetic information on TPA strains in several countries [7][8][9][10][11][12][13][14] , those data have not necessarily been accumulated enough for comprehension of the overall aspects of the TPA circulations in the world.…”

Molecular typing of T. pallidum clinical isolates and their resistance to macrolides in the Russian Federation during 2018–2019

“…Results of the molecular typing and determination of the genetic marker of resistance to macrolide antibiotics in clinical isolates of T. pallidum from the subjects of the Russian Federation (2018-2019) взаимного расположения повторов с разными нуклеотидными последовательностями [18]. Аналогичный подход в дальнейшем может быть использован и для исследования генов tprII, вариабельность которых, вероятно, не исчерпывается расположением сайтов рестрикции [19]. Решение перечисленных вопросов позволит перевести молекулярное типирование T. pallidum в формат мультилокусного секвенирования, что при сохранении действующего деления на типы и субтипы с соответствующей номенклатурой предположительно должно повысить разрешающую чувствительность метода.…”