Contemporary syphilis is characterised by rapid global spread of pandemicTreponema pallidumlineages

Abstract

Syphilis is an important sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The last two decades have seen syphilis incidence rise in many high-income countries, yet the evolutionary and epidemiological relationships that underpin this are poorly understood, as is the global T. pallidum population structure. We assembled a geographically and temporally diverse collection of clinical and laboratory samples comprising 726 T. pallidum genomes. We used detailed phylogenetic analysis and clustering to show that syphilis globally can be described by only two deeply branching lineages, Nichols and SS14. We show that both of these lineages can be found circulating concurrently in 12 of the 23 countries sampled. To provide further phylodynamic resolution we subdivided Treponema pallidum subspecies pallidum into 17 distinct sublineages. Importantly, like SS14, we provide evidence that two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analysis showed that recent isolates circulating in 14 different countries were genetically identical in their core genome to those from other countries, suggesting frequent exchange through international transmission pathways. This contrasts with the majority of samples collected prior to 1983, which are phylogenetically distinct from these more recently isolated sublineages. Bayesian temporal analysis provided evidence of a population bottleneck and decline occurring during the late 1990s, followed by a rapid population expansion a decade later. This was driven by the dominant T. pallidum sublineages circulating today, many of which are resistant to macrolides. Combined we show that the population of contemporary syphilis in high-income countries has undergone a recent and rapid global expansion.

Genome sequencing of 196 Treponema pallidum strains from six continents reveals additional variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar

“…The result of this is that, although we gained a broader picture of worldwide diversity, some regions (North America, western Europe, eastern Asia) continue to be overrepresented, while other regions (Africa – particularly Sub-Saharan Africa, which bears the largest share of cases worldwide – and South Asia and South America) are still vastly under-sampled. However, an important takeaway from our study as well as the recent paper from Beale et al (63) is that the general understanding that SS14 represents the vast majority of circulating strains may require revisiting. Although the island nation of Madagascar is unlikely truly representative of the diversity of strains currently circulating in Sub-Saharan Africa, particularly because the samples are 15-20 years old, our finding that 99% of Malagasy strains belong to the Nichols clade, coupled with Beale et al .’s discovery of Nichols strains circulating in Zimbabwe and South Africa (63) strongly suggests widespread circulation of Nichols clade TPA in Africa.…”

“…However, an important takeaway from our study as well as the recent paper from Beale et al (63) is that the general understanding that SS14 represents the vast majority of circulating strains may require revisiting. Although the island nation of Madagascar is unlikely truly representative of the diversity of strains currently circulating in Sub-Saharan Africa, particularly because the samples are 15-20 years old, our finding that 99% of Malagasy strains belong to the Nichols clade, coupled with Beale et al .’s discovery of Nichols strains circulating in Zimbabwe and South Africa (63) strongly suggests widespread circulation of Nichols clade TPA in Africa. Clearly, increased sampling must be a priority to enable understanding of syphilis epidemiology in Africa, and to ensure a vaccine covers strains circulating in the regions most hard hit by the modern pandemic.…”

“…In recent years, T. pallidum genomics has been significantly advanced by projects aimed at studying the origin and spread of strains responsible for the modern syphilis pandemic (24,26,36,39,63), as well as the emergence of azithromycin resistance (24,26,63). Increasingly the challenge in T. pallidum genomics will be attaining complete genomic sequences from undersampled regions, associating genomic sequencing with spirochete biochemical functions, and gaining actionable insights into T. pallidum evolution that inform vaccine design.…”

“…With these goals, we generated 196 near-complete T. pallidum genomes from diverse locations, including three countries – Peru, Italy, and Madagascar – with no previous complete genomes publicly available. Peruvian samples (n=9) belonged exclusively to the SS14 Omegà subclade, which contains samples collected worldwide and corresponds to the largest SS14 sub-lineage in a recent analysis of SNPs in TPA strains (63). Eight of the ten Italian strains also belonged to the Omegà subclade.…”

“…In our study, as in other recent global T. pallidum subsp. pallidum genomics initiatives (24,63), samples were collected and sequenced based on availability rather than representing an even distribution based on global burden of disease. The result of this is that, although we gained a broader picture of worldwide diversity, some regions (North America, western Europe, eastern Asia) continue to be overrepresented, while other regions (Africa – particularly Sub-Saharan Africa, which bears the largest share of cases worldwide – and South Asia and South America) are still vastly under-sampled.…”