Cracking syphilis code: Genome sequencing reveals transmission secrets

By Dr. Priyom Bose, Ph.D.Sep 20 2023Reviewed by Benedette Cuffari, M.Sc.

A recent Lancet Microbe study used whole genome sequencing to gain epidemiological insights into syphilis transmission.

Study: Genomic epidemiology of syphilis in England: a population-based study. Image Credit: Tatiana Shepeleva / Shutterstock.com

Background

Syphilis is a sexually transmitted infection (STI) that is treatable with medication. STIs are bacterial infections caused by Treponema pallidum subspecies pallidum.

Since the beginning of the 21^st century, there has been an increase in the number of syphilis cases, particularly in high-income countries. In fact, new syphilis cases jumped from 3,011 in 2012 to 8,011 in 2019 in England. This increase has been associated with bisexual, gay, and other men who have sex with men (GBMSM) engaging in high-risk sexual behavior.

An increase in syphilis has also been recorded in heterosexual men and women, which indicates the possibility of vertical transmission causing congenital syphilis. Between 2015 and 2020, about 24 cases of congenital syphilis have been identified in England. In some regions of England, an increase in syphilis cases was recorded among women and GBMSM, thus indicating an overlapping sexual network as the underlying cause for broader dissemination.

Epidemiological surveillance has provided insufficient data about syphilis transmission dynamics. For example, analysis of spatiotemporally clustered cases suggests a single outbreak and transmission chain; however, this outbreak could also have originated from unrelated transmission networks.

Molecular techniques help determine genetically related T. pallidum strains. However, this method cannot accurately define strain clusters that could indicate epidemiologically important timelines.

The application of whole genome sequencing (WGS) has shown the global presence of two co-circulating T. pallidum lineages, including Nichols and SS14. These lineages have been subdivided into seventeen sublineages and singletons.

About the study

The current study used WGS to understand the transmission dynamics of syphilis at national and regional levels. T. pallidum-positive genomic DNA samples were obtained from the United Kingdom Health Security Agency (UKHSA), London, and five laboratories that perform in-house molecular T. pallidum diagnostic testing.

All relevant data were retrieved from the Genitourinary Medicine Clinic Activity Dataset (GUMCAD). Phylogenomic analyses of the genomic samples were performed.

Local lineages of T. pallidum samples were identified along with their transmission clusters based on location or sexual orientation. Furthermore, the distribution and frequency of macrolide resistance-conferring alleles among T. pallidum sublineages were evaluated.

Study findings

The current study linked spatiotemporal, demographic, and behavioral metadata of syphilis patients with previously generated T. pallidum genomes from patients diagnosed with syphilis between 2012 and 2018 in England.

A total of 497 samples were identified between January 1, 2012, and October 31, 2018, that were considered suitable for WGS. Of these samples, complete genomes of 240 samples were recovered, 220 of which were ultimately considered for the analysis.

About 90% of the samples were from men, 4% from women, and the rest were of unknown gender. Most samples were from London, followed by southeast England, northeast England, and southwest England. Moreover, about 76% of genomes were from GBMSM, 40% of whom lived in London and were human immunodeficiency virus (HIV) positive.

Various English sublineages were identified; however, global sublineages one and 14 were the dominant groups. Although both groups are resistant to macrolides, they exhibit a differential patient sociodemographic and spatiotemporal profiles.

Sublineage one is associated with a greater diversity of sexual orientation, HIV status, gender, and age, whereas sublineage 14 is mainly linked to older GBMSM. Another demographic difference between both groups is that sublineage one has been identified in all regions of England, whereas sublineage 14 has been primarily identified in London and not the northern regions of England, thus indicating that both sublineages represent distinctive sexual transmission networks.

Since both sublineages one and 14 comprise patients with and without HIV, HIV status is not significantly correlated with the transmission of syphilis. In three instances, discrete heterosexual transmission networks or clusters were identified.

However, in most cases, genetic clusters linked to GBMSM indicated spatiotemporal diversity. Differences in spatiotemporal diversity indicate differential partner-seeking behavior between GBMSM and heterosexual people.

A mixed cluster was found with identical core genomes, most of which were represented by GBMSM. The identification of discrete clusters revealed the possibility of resolving local transmission chains for T. pallidum based on detailed epidemiological data.

Conclusions

The current study has some limitations, including the small sample size as compared to the total number of syphilis cases during the study period. There is a high possibility of the overrepresentation of samples from GBMSM in the national genome database.

Despite these limitations, the study findings indicate the effectiveness of WGS in identifying transmission clusters for epidemiological follow-up. This finding is invaluable for analyzing putative outbreaks and formulating effective interventions to protect people from syphilis.