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Key Points Pathogenic treponemes are clonal, unculturable, highly invasive bacteria that cause venereal syphilis, yaws, endemic syphilis and pinta — multi-stage infections that have many similarities, but can be differentiated based on clinical, epidemiological, geographical and, most recently, genomic criteria. Only Treponema pallidum subsp. pallidum is transmitted through sexual activity. Key to the capacity of the syphilis spirochete for immune evasion and thus 'stealth pathogenicity' is its unusual outer membrane, which lacks lipopolysaccharide and contains an extremely low density of integral membrane proteins and a paucity of surface-exposed lipoproteins. The production of opsonic antibodies against low-abundance surface antigenic targets is believed to be essential for control of syphilitic infection. In recent years, considerable progress has been made in defining the repertoire of β-barrel-forming rare outer membrane proteins of the syphilis spirochete and the mechanisms by which the bacterium seems to limit the exposure of surface molecules to the antibody-mediated defences of the host. During the course of genomic reduction, T. pallidum has undergone adaptations that enable it to acquire all of its required nutrients from its obligate human host and optimize their usage in various niches, while coping with exogenous and endogenous stresses. The genome of T. pallidum encodes several alternative sigma factors and other regulatory molecules or pathways that collectively point to a previously unsuspected capacity to intricately regulate gene expression in diverse microenvironments. Comparative genomics has enabled investigators to identify 'hotspots' for sequence variation that probably explain differences in virulence potential and tissue tropisms among the pathogenic treponemes; many of these hotspots are located in proteins that are known or predicted to reside at the host–pathogen interface. Treponema pallidum , the causative agent of syphilis, is extremely well adapted to its host. In this Review, Radolf and colleagues discuss how this pathogen has streamlined its cell envelope, metabolism and genome to thrive and cause disease in humans. The past two decades have seen a worldwide resurgence in infections caused by Treponema pallidum subsp. pallidum , the syphilis spirochete. The well-recognized capacity of the syphilis spirochete for early dissemination and immune evasion has earned it the designation 'the stealth pathogen'. Despite the many hurdles to studying syphilis pathogenesis, most notably the inability to culture and to genetically manipulate T. pallidum , in recent years, considerable progress has been made in elucidating the structural, physiological, and regulatory facets of T. pallidum pathogenicity. In this Review, we integrate this eclectic body of information to garner fresh insights into the highly successful parasitic lifestyles of the syphilis spirochete and related pathogenic treponemes.

In spite of its immutable susceptibility to penicillin, Treponema pallidum ( T . pallidum ) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T . pallidum strains–including 191 T . pallidum subsp. pallidum –sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T . pallidum subsp. pallidum and subsp. endemicum , shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543–1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens.

The bacterium Treponema pallidum pertenue causes yaws in humans and nonhuman primates. We describe 33% T. pallidum pertenue seropositivity in 9 species of nonhuman primates in Uganda and Rwanda, seroconversion during a lethal outbreak and a novel bacterial genomic lineage. Yaws may threaten both public health and conservation in the region.

Previous in vitro long-term cultivation studies of Treponema pallidum subsp. pallidum ( T. pallidum ) strains have indicated potential differences in the length of generation times among individual strains. In the present study, we have determined in vitro growth rates of seven T. pallidum strains including three from the Nichols-like cluster (DAL-1, Madras, and Haiti B) and four from the SS14-like cluster (Mexico A, SS14, Grady, and Philadelphia 1). Despite the observed considerable variability, the results of standard subcultures identified growth differences between the two clusters during the long-term cultivation. Furthermore, in vitro monocultures with defined inoculum revealed differences among individual strains. During three week-long binary co-cultivations of seven strains ( n  = 21), different growth rates were confirmed for individual strains ( p  < 0.001) using PCR amplicon sequencing of genomic regions differentiating treponemal-pairs. The order of strains by decreasing growth rate in vitro was DAL-1, Madras, Mexico A, Haiti B, SS14, Grady, and Philadelphia 1. While the generation time of strain DAL-1 was 32.97 h, the slowest strain, Philadelphia 1, had generation time 43.5 h. These experiments revealed significant physiological differences between the T. pallidum strains, which may also be involved in the variable presentation of syphilis symptoms observed in previous decades.

Syphilis, which is caused by the sexually transmitted bacterium Treponema pallidum subsp. pallidum , has an estimated 6.3 million cases worldwide per annum. In the past ten years, the incidence of syphilis has increased by more than 150% in some high-income countries, but the evolution and epidemiology of the epidemic are poorly understood. To characterize the global population structure of T. pallidum , we assembled a geographically and temporally diverse collection of 726 genomes from 626 clinical and 100 laboratory samples collected in 23 countries. We applied phylogenetic analyses and clustering, and found that the global syphilis population comprises just two deeply branching lineages, Nichols and SS14. Both lineages are currently circulating in 12 of the 23 countries sampled. We subdivided T. p. pallidum into 17 distinct sublineages to provide further phylodynamic resolution. Importantly, two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analyses revealed examples of isolates collected within the last 20 years from 14 different countries that had genetically identical core genomes, which might indicate frequent exchange through international transmission. It is striking that most samples collected before 1983 are phylogenetically distinct from more recently isolated sublineages. Using Bayesian temporal analysis, we detected a population bottleneck occurring during the late 1990s, followed by rapid population expansion in the 2000s that was driven by the dominant T. pallidum sublineages circulating today. This expansion may be linked to changing epidemiology, immune evasion or fitness under antimicrobial selection pressure, since many of the contemporary syphilis lineages we have characterized are resistant to macrolides. Global syphilis prevalence has been increasing. Sequencing and analysis of a global collection of 726 Treponema pallidum samples reveal globally circulating lineages linked to a rapid expansion occurring since the end of the twentieth century.

In this randomized, controlled trial, persons with early syphilis received a single treatment or three treatments with benzathine penicillin G at a dose of 2.4 million units. No benefit was seen with the additional doses.

Investigation of Treponema pallidum subsp. pallidum , the spirochete that causes syphilis, has been hindered by an inability to culture the organism continuously in vitro despite more than a century of effort. In this study, long-term logarithmic multiplication of T. pallidum was attained through subculture every 6 to 7 days and periodic feeding using a modified medium ( T. pallidum culture medium 2 [TpCM-2]) with a previously described microaerobic, rabbit epithelial cell coincubation system. Currently, cultures have maintained continuous growth for over 6 months with full retention of viability as measured by motility and rabbit infectivity. This system has been applied successfully to the well-studied Nichols strain of T. pallidum , as well as to two recent syphilis isolates, UW231B and UW249B. Light microscopy and cryo-electron microscopy showed that in vitro -cultured T. pallidum retains wild-type morphology. Further refinement of this long-term subculture system is expected to facilitate study of the physiological, genetic, pathological, immunologic, and antimicrobial susceptibility properties of T. pallidum subsp. pallidum and closely related pathogenic Treponema species and subspecies. IMPORTANCE Syphilis, a sexually transmitted disease with a global distribution, is caused by a spiral-shaped bacterium called Treponema pallidum subspecies pallidum . Previously, T. pallidum was one of the few major bacterial pathogens that had not been cultured long-term in vitro (in a test tube), greatly hindering efforts to better understand this organism and the disease that it causes. In this article, we report the successful long-term cultivation of T. pallidum in a tissue culture system, a finding that is likely to enhance our ability to obtain new information applicable to the diagnosis, treatment, and prevention of syphilis. Syphilis, a sexually transmitted disease with a global distribution, is caused by a spiral-shaped bacterium called Treponema pallidum subspecies pallidum . Previously, T. pallidum was one of the few major bacterial pathogens that had not been cultured long-term in vitro (in a test tube), greatly hindering efforts to better understand this organism and the disease that it causes. In this article, we report the successful long-term cultivation of T. pallidum in a tissue culture system, a finding that is likely to enhance our ability to obtain new information applicable to the diagnosis, treatment, and prevention of syphilis.

Worldwide, more than 90% of contemporary syphilis strains belong to SS14-like clade. This study aimed to describe the molecular profile of circulating Treponema pallidum subsp. pallidum (TPA) strains in Barcelona, Spain, from 2021 to 2023 building upon our report in 2015 which showed that 94.8% of typed strains belonged to the SS14 clade. Multilocus sequence typing (MLST) was conducted on TPA-positive samples obtained from swab samples by sequencing the tp0136, tp0548, and tp0705 loci. Strains were classified as Nichols-like or SS14-like clade. Macrolide and tetracycline resistance‑associated mutations were determined through analysis of 23S rDNA and 16S rRNA gene sequences. Of the 96 typeable samples, 47.9% belonged to SS14-like and 52.1% to the Nichols-like. Fourteen haplotypes were identified, with ST26 representing 43.8% of the samples, distributed across 11 haplotypes in the SS14-like and 3 haplotypes in the Nichols-like. All the samples showed macrolide resistance-associated mutations, while none exhibited tetracycline-associated mutations. Our findings revealed a substantial shift in the proportion of TPA clades within the Barcelona population from 2021 to 2023, characterized by a higher proportion of Nichols-like strains compared to 2015 and international trends. The varying temporal and geographical trends underscore the need for regular surveillance to understand regional variations in syphilis and strengthen control programs.

Of 604 Treponema pallidum (syphilis) strains sampled from 13 U.S. states, Washington, D.C., and two Canadian provinces from 2017 through 2023, a total of 599 (99.2%) had genotypic resistance to azithromycin.

Syphilis is a fascinating and perplexing infection, with protean clinical manifestations and both diagnostic and management ambiguities. Treponema pallidum subsp. pallidum, the agent of syphilis, is challenging to study in part because it cannot be cultured or genetically manipulated. Here, we review recent progress in the application of modern molecular techniques to understanding the biological basis of this multistage disease and to the development of new tools for diagnosis, for predicting efficacy of treatment with alternative antibiotics, and for studying the transmission of infection through population networks.