Genomic epidemiology of syphilis in England: a population-based study

Abstract

Background: Syphilis is a sexually transmitted bacterial infection caused by Treponema pallidum subspecies pallidum. Since 2012, syphilis rates have risen dramatically in many high-income countries, including England. Although this increase in syphilis prevalence is known to be associated with high-risk sexual activity in gay, bisexual, and other men who have sex with men (GBMSM), cases are rising in heterosexual men and women. The transmission dynamics within and between sexual networks of GBMSM and heterosexual people are not well understood. We aimed to investigate if whole genome sequencing could be used to supplement or enhance epidemiological insights around syphilis transmission.

Methods: We linked national patient demographic, geospatial, and behavioural metadata to whole T pallidum genome sequences previously generated from patient samples collected from across England between Jan 1, 2012, and Oct 31, 2018, and performed detailed phylogenomic analyses.

Findings: Of 497 English samples submitted for sequencing, we recovered 240 genomes (198 from the UK Health Security Agency reference laboratory and 42 from other laboratories). Three duplicate samples (same patient and collection date) were included in the main phylogenies, but removed from further analyses of English populations, leaving 237 genomes. 220 (92·8%) of 237 samples were from men, nine (3·8%) were from women, and eight (3·4%) were of unknown gender. Samples were mostly from London (n=118 [49·8%]), followed by southeast England (n=29 [12·2%]), northeast England (n=24 [10·1%]), and southwest England (n=15 [6·3%]). 180 (76·0%) of 237 genomes came from GBMSM, compared with 25 (10·5%) from those identifying as men who have sex with women, 15 (6·3%) from men with unrecorded sexual orientation, nine (3·8%) from those identifying as women who have sex with men, and eight (3·4%) from people of unknown gender and sexual orientation. Phylogenomic analysis and clustering revealed two dominant T pallidum sublineages in England. Sublineage 1 was found throughout England and across all patient groups, whereas sublineage 14 occurred predominantly in GBMSM older than 34 years and was absent from samples sequenced from the north of England. These different spatiotemporal trends, linked to demography or behaviour in the dominant sublineages, suggest they represent different sexual networks. By focusing on different regions of England we were able to distinguish a local heterosexual transmission cluster from a background of transmission in GBMSM.

Interpretation: These findings show that, despite extremely close genetic relationships between T pallidum genomes globally, genomics can still be used to identify putative transmission clusters for epidemiological follow-up. This could be of value for deconvoluting putative outbreaks and for informing public health interventions.

Funding: Wellcome funding to the Sanger Institute, UK Research and Innovation, National Institute for Health and Care Research, European and Developing Countries Clinical Trials Partnership, and UK Health Security Agency.

Figure 1

Population structure of English Treponema pallidum genomes according to phylogenetic sublineages and associated patient characteristics (A) Minimum spanning tree visualisation of genetic relationships between samples from England. Node size corresponds to the number of identical genome samples in a cluster, and edge length (with number) to the number of substitutions between identical genome sample clusters (where edges were longer than 12 substitutions, these have been shortened; this is indicated by dashed lines). Numbers in parentheses indicate total sample count for each sublineage. Primary lineage (SS14/Nichols) is indicated by encompassing ellipses; sublineage 6 diverges from other Treponema pallidum subspecies pallidum close to the root, and has previously been classified as Nichols. (B) Samples per collection year per sublineage. (C) Total sample counts per sublineage. Bar plots show proportion of each group. (D) Proportion of each group by sexual orientation. (E) Proportion of each group by HIV status. (F) Proportion of each group by age group (numbers indicate exact sample counts). SNP=single nucleotide polymorphism. MSW=men who have sex with women. GBMSM=gay, bisexual, and other men who have sex with men. WSM=women who have sex with men. MUnknown=men with unrecorded sexual orientation.

Figure 2

Geographical distribution of English genome samples and according to phylogenetic sublineages (A) Proportion of samples from each UKHSA region of England by Treponema pallidum subspecies pallidum lineage. (B) Proportion of samples in each public health region of England for the two most common T pallidum sublineages. (C) Distribution of sample collection years. (D) Total sample counts. (E) Proportion of samples from each region by lineage. (F) Proportion of samples from each region by sublineage. UKHSA=UK Health Security Agency.

Figure 3

Spatiotemporal and genomic clustering analysis of samples from northeast England (A) Minimum spanning tree visualisation of genomic relationships between samples in northeast England. Node size corresponds to the number of identical samples, and edge length (with number) to the number of substitutions between clusters (where edges were longer than 3 substitutions, these have been shortened, indicated by dashed lines). Nodes are coloured by proportion of patient gender orientation). Clusters were defined by connections to another sample within two pairwise-single nucleotide polymorphisms. Clusters 1 and 2 appear to be dominated by GBMSM populations, while Cluster 3 contains only patients identifying as heterosexual. (B) Time-scaled sublineage 1 tree of global samples indicates that the GBMSM-associated cluster 1 is a globally distributed cluster, and that the northeast samples are polyphyletic. (C) Time-scaled subtree of global samples sharing a common ancestor with cluster 2 indicates a close relationship with two samples from London, and more distantly with those from southwest England and Portugal. (D) Time-scaled subtree of global samples sharing a common ancestor with the heterosexual-associated cluster 3 suggests the northeast England samples are closely related to each other, but not to any others, with the closest related strain found in Hungary. This could imply a historic importation from another country, followed by local circulation. MSW=men who have sex with women. GBMSM=gay, bisexual and other men who have sex with men. WSM=women who have sex with men. UKHSA=UK Health Security Agency.