Immunisation with the glycolytic enzyme enolase inhibits dissemination of Treponema pallidum in C57BL/6 mice.

Treponema pallidum (T. pallidum), an obligate extracellular bacterium, is the causative agent of sexually transmitted bacterial diseases. In this study, the glycolytic enzyme enolase (Tp Eno) of T. pallidum were injected intramuscularly into C57BL/6 mice, resulting in higher levels of specific anti-Tp Eno antibodies and Tp Eno-specific splenocyte proliferation than those in the mice immunized with recombinant protein Tp Eno. Cytokine (IL-4, IL-6, IL-10, IFN-γ, and TNF-α) analysis of splenocytes showed that the Tp Eno could slightly trigger the Th1-biased immune response. Furthermore, immunization of mice with Tp Eno elicited a significant production of IFN-γ by CD4+ T-cells in the spleen. Subsequently, mice were inoculated intradermally (between the scapulae), intraperitoneally, intrarectally and via the corpora cavernosa with 2.5 × 106 organisms per site (1 × 107 total organisms). The bacterial organ burden detected in the blood, spleen, liver, testes or brain of immunized mice suggested that Tp Eno enhances protective immunity to inhibit T. pallidum colonization in distal tissues. Therefore, Tp Eno vaccination enhances Tp Eno-specific immunogenicity and provides protection against T. pallidum dissemination.

Injection drug use and sexually transmitted infections among men who have sex with men: A retrospective cohort study at an HIV/AIDS referral hospital in Tokyo, 2013-2022.

Men who have sex with men (MSM) who use injection drugs (MSM-IDU) are at high risk of sexually transmitted infections (STIs), but the long-term incidence is unclear. We conducted a single-centre retrospective cohort study using the clinical records of non-haemophilia men with human immunodeficiency virus (HIV) who visited the Institute of Medical Science, the University of Tokyo (IMSUT) Hospital, located in Tokyo, Japan, from 2013 to 2022. We analysed 575 patients including 62 heterosexual males and 513 MSM patients, of whom 6.8% (35/513) were injection drug use (IDU). Compared to non-IDU MSM, MSM-IDU had a higher incidence of hepatitis C virus (HCV) (44.8 vs 3.5 /1,000 person-years (PY); incidence rate ratio (IRR) [95% confidence interval (95% CI)], 12.8 [5.5-29.3], p < 0.001) and syphilis (113.8 vs 53.3 /1,000 PY; IRR, 2.1 [1.4-3.1], p < 0.001). The incidence of other symptomatic STIs (amoebiasis, chlamydia, and gonorrhoea infections) was <4/1,000 PY. In multivariable Poisson regression analysis, HCV incidence was associated with MSM (IRR, 1.8 × 106 [9.9 × 105-3.4 × 106], p < 0.001), IDU (IRR, 10.1 [4.0-25.6], p < 0.001), and syphilis infection during the study period (IRR, 25.0 [1.2-518.3]/time/year, p < 0.001). Among men with HIV, the prevalence of IDU in MSM and the long-term incidence of STIs in MSM-IDU were high. IDU and sexual contact are important modes of transmission of HCV among HIV-infected MSM in Tokyo.

Differential Serodiagnostics of Latent Stages of Syphilis Based on Measuring IgG and IgM Levels towards Extended Panel of Recombinant Antigens of T. pallidum.

Immunochips containing 12 recombinant antigens of T. pallidum (Тр15, Тр17, Тр47, TmpA, Тр0163, Тр0277, Тр0319, Тр0453, Тр0684, Тр0965, Тр0971, and Тр1038) were prepared to assay for IgG and IgM in serum samples (n=68) of healthy individuals and patients with the latent stages of syphilis. The linear discriminant analysis of detected IgG and IgM differentiated three groups of serum samples as 1) early latent syphilis; 2) seroresistant early latent syphilis; and 3) late latent syphilis with overall differentiation potency of 95.6% (88.9-100%). The samples of all syphilis patients were differentiated from the samples of healthy individuals with 100% specificity.

[Сomparison of immunoarrays for syphilis diagnostics produced by co-polymerization immobilization and non-contact printing techniques.]

The aim of the study was to investigate the characteristics of immunoarrays (microarrays) produced by co-polymerization immobilization and non-contact printing techniques for enhancing the capacities of syphilis diagnostics. In diagnostic context immunoarrays of both protein immobilization techniques have shown high sensitivity and specificity together with potency to differentiate syphilis stages in serologic assays. The article discloses the advantages and limitations of non-contact printing techniques as well as the results and problems revealed in the study. Solution of these problems in future may provide the development of new serodiagnostic tools with higher accuracy of the results.

Circulation of Distinct Treponema pallidum Strains in Individuals with Heterosexual Orientation and Men Who Have Sex with Men.

Human treponematosis is caused by various pathogenic Treponema pallidum subspecies, including T. pallidum subsp. pallidum, T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and Treponema carateum The global prevalence of syphilis has been increasing since the 2000s. Men account for more than 90% of the cases, with the majority being men who have sex with men (MSM). In Japan, the increase in the number of syphilis patients began in 2011, a 10-year delay from the global trend. In 2017, a total of 5,829 syphilis cases (3,934 men and 1,895 women) were reported, with an outstanding increase in cases among young adult women; the number reported for women age 15 to 20 years was 1,100. Hence, a molecular epidemiological study was conducted on circulating T. pallidum strains using two strain typing methods, the enhanced CDC method and sequencing-based molecular typing. Clinical specimens from 95 adults suspected of syphilis were collected from September 2013 to August 2017 in Osaka, Japan. T. pallidum DNA was detected in specimens from 25 males and 11 females, including seven MSM. The majority of the heterosexual patients (66.7% and 90.9% of males and females, respectively) were positive for 14d/f-SSR8. In contrast, the genotypes identified in the MSM group were significantly divergent. T. pallidum subsp. endemicum was notably identified in two MSM patients. Macrolide-sensitive or Nichols-like strains were significantly associated with the MSM group. These data suggest that distinct T. pallidum strains were circulating in the heterosexual and MSM groups. Our findings imply that independent factors may contribute to the increased syphilis prevalence in heterosexual and MSM populations.

The resurgence of syphilis in high-income countries in the 2000s: a focus on Europe.

Syphilis can cause severe complications and sequelae. Following a decrease in reported cases in European Union/European Economic Area (EU/EEA) and other high-income countries in the 1980s and 1990s as a result of the HIV epidemic and ensuing changes in sexual behaviour, trends started to increase in the 2000s in a number of EU/EEA Member States with higher rates among men and a large proportion of cases reported among men who have sex with men (MSM), particularly HIV-positive MSM. Trends in EU/EEA Member States vary however with some countries continuing to report decreases in the number of reported cases (mostly in the Eastern part of EU/EEA) whereas many Western European countries report increasing numbers of cases. Increasing rates among women, although still relatively low, have been observed in a number of countries leading to concerns around mother-to-child transmission of syphilis and congenital syphilis. Similar overall trends are observed in other high-income countries with the exception of Japan where rates among heterosexual men and women have been rising at alarming levels. Control of syphilis requires use of comprehensive, evidence-based strategies which take into account lessons learned from previous control efforts as well as consideration of biomedical interventions.

Neurosyphilis prevalence at a Portuguese stroke unit care.

INTRODUCTION: Syphilis is a systemic human disease which is caused by infection with the spirochete Treponema pallidum. It is spread worldwide, and there has recently been an increase in its incidence. Neurosyphilis (NS) can have a variety of presentations; meningovascular NS is a specific affection of the Treponema which occurs in an early stage after the primary infection, causing an inflammatory arteriopathy which may result in an ischemic stroke. As a rare manifestation of syphilis, there are few prevalence and epidemiological studies, and data are almost non-existent. The objective of this study is to analyse the prevalence of meningovascular NS in a stroke unit in a tertiary hospital. METHODS: A descriptive retrospective study was carried out over a period of 44 months in a stroke unit. All patients admitted had neurological symptoms compatible with a vascular event, and routine blood tests including infectious screening were performed. Those with positive test results for syphilis were identified and proceeded to lumbar puncture to CSF cytochemical analysis and VDRL. NS was categorized as confirmed or probable (using CDC criteria). RESULTS: A total of 525 patients were admitted, and 62.53% were submitted to a routine screening for syphilis. A total of 309 patients (95.67%) revealed a negative screening; 12 patients (3.72%) had a positive syphilis serology. Among the 12 patients with positive screening, a single case of NS (0.31%) was identified. CONCLUSION: We observed a low prevalence of NS (0.31%), but this result was surprisingly higher than what was expected in an elderly population.

[Diagnostic imminoarray assay for characterization of immunoglobulin igg and igm level in syphilis patients serum towards 12 recombinant antigens of t. pallidum before and after the therapy.]

The aim of the study was to characterize the dynamics of immunoglobulin IgG and IgM level in syphilis patients serum at different stages of the disease before and after the therapy towards 12 diagnostic antigens of T. pallidum in an microarray assay and to evaluate these data as possible prognostic markers. The dynamics of immunoglobulin IgG and IgM level was measured in the reaction of indirect immunofluorescence using microarray and compared to the results of non-treponemal RPR test and treponemal tests as EIA and reaction of passive hemagglutination. In microarray assay diagnostically high level of IgM in patients with primary, secondary and early latent and late latent syphilis decreased dramatically to zero after the successful therapy. Continuously high level of IgM after the therapy proposes the persistence of infection agents in the organism and points out the need of additional antimicrobial treatment. In most of the cases anti-treponemal IgG level also declined after the successful therapy and this confirms the appropriate treatment. The results of microarray assay coincide with the results of other mentioned laboratory tests for syphilis diagnostics. Microarray assay with the recombinant T. pallidum antigens gives the perspective for creating methods with wider spectrum of diagnostic and therapy control options using the IgM immunoglobulin level as a marker for successful syphilis treatment.

Clinical and Biological Characteristics of 40 Patients With Neurosyphilis and Evaluation of Treponema pallidum Nested Polymerase Chain Reaction in Cerebrospinal Fluid Samples.

BACKGROUND: Syphilis remains a significant public health problem. We conducted a prospective study to define more precisely the clinical and biological characteristics of patients with neurosyphilis (NS), and we assessed the diagnostic value of nested polymerase chain reaction (PCR) testing for Treponema pallidum in cerebrospinal fluid (CSF) samples. METHODS: From 2001 to 2013, we included 40 patients (90% men; 45% infected with human immunodeficiency virus) with NS, defined as syphilis with neurological and/or ophthalmological symptoms and CSF abnormalities. RESULTS: Thirty patients (75%) had early, 5 (12.5%) had late, and 5 had meningovascular NS. Twenty-four patients (80%) with early NS had ophthalmological symptoms, 14 (47%) had neurological symptoms, and 8 (26%) had both. All patients with meningovascular NS had only neurological symptoms. All patients with late NS had neurological symptoms, and 2 (40%) also had ocular symptoms. Ophthalmological symptoms were present in 65% of all patients with NS, and neurological symptoms in 60%. Seventeen patients (42.5%) had CSF white blood cell counts >20/µL (mean, 57/µL), and 27 (67.5%) had high CSF protein levels (>0.5 g/L; mean value, 1 g/L). CSF PCR results were positive in 42%, and CSF VDRL results in 30%. The nested PCR assay had an overall sensitivity of 42.5%, a specificity of 97%, a positive predictive value of 77%, and a negative predictive value of 86%. CONCLUSIONS: Early NS is the most frequent presentation, with an overrepresentation of polymorphous ophthalmological symptoms. PCR is highly specific and of potential value when used with other biological parameters.

Detection of Treponema pallidum Sp. Pallidum DNA in Cerebrospinal Fluid (CSF) by Two PCR Techniques.

BACKGROUND: Laboratory diagnosis of neurosyphilis is complicated especially when it is asymptomatic, no single laboratory test result being appropriate to diagnose central nervous system infectivity caused by Treponema pallidum. Our objective was to evaluate two polymerase chain reaction (PCR) techniques for the detection of T. pallidum DNA in the cerebrospinal fluid (CSF) of patients with syphilis. METHODS: One hundred twenty-four CSF samples from patients with reactive blood tests for syphilis were obtained. Two PCR techniques (47-PCR, polA-PCR) were used to detect T. pallidum DNA. The laboratory criteria used for the diagnosis of neurosyphilis to which the PCR techniques were compared were those recommended by the IUSTI: 2008 European guidelines on the management of syphilis. RESULTS: Treponema pallidum DNA was detected amplified in 37 of 124 (29.8%) and 30 of 124 (24.2%) samples with the 47-PCR and polA-PCR, respectively. Sensitivities were 75.8% and 69.7% and specificities 86.8% and 92.3%, respectively, for 47-PCR and polA-PCR techniques, respectively. The three CSF samples of patients with primary syphilis did not fulfill the criteria of neurosyphilis and DNA was only detected in one by the 47-PCR. In samples from secondary syphilis and neurosyphilis, three of nine and nine of nine respectively, results were coincident for the two PCR techniques and neurosyphilis criteria. Major discrepancies between the two PCR techniques and neurosyphilis diagnostic criteria were observed in latent syphilis. CONCLUSION: Beyond some limitations of the study, which are discussed here, both PCR techniques seem to be useful for the diagnosis of neurosyphilis, although 47-PCR presents a higher sensitivity and polA-PCR a higher specificity.

Prevalence of HIV, Treponema pallidum and Their Coinfection in Men Who Have Sex with Men, Medellín-Colombia.

Introduction: In Colombia, HIV and gestational syphilis are notifiable events; however, they are poorly investigated infections in men who have sex with men (MSM). Objective: To determine the prevalence of HIV, Treponema pallidum, and their co-infection in MSM treated at a Health Services Provider Institution (HSPI) specialized in infectious diseases from Medellín. Methods: Cross-sectional study with 3454 MSM. Prevalence was determined with its 95% confidence interval; associated factors were identified using Fisher's Exact test, Pearson's Chi-square, and trend Chi-square. Multivariate adjustment was performed using logistic regression. Analyses were performed using SPSS 29.0. Results: The prevalence of HIV was 5.7%, T. pallidum 0.7%, and co-infection 0.6%. The prevalence of HIV was higher in MSM aged between 24-40 years (7.5%), with technical or university studies (10.0%), without health insurance affiliation (12.4%), and those who have had a sexual partner with HIV (36.2%). T. pallidum was higher in MSM without health insurance affiliation (3.4%), who had sexual relations with people diagnosed with an STI (5.9%), and a sexual partner with HIV (12.1%). Co-infection was higher in MSM without health insurance affiliation (2.7%), and those who had a partner with HIV (11.2%). Conclusion: Compared with the general Colombian population, MSM have a higher risk of HIV, but are similar to T. pallidum. The identification of the main associated factors in each infection demonstrates the need to prioritize subgroups of MSM that show greater vulnerability to these events. This research demonstrates the urgency of implementing health education strategies in MSM who have a sexual partner with HIV or other STIs. Large gaps were also evident in the magnitude of the three events according to the health insurance affiliation regime, which demonstrates problems of social and health injustice, especially with MSM without health insurance affiliation.

Screening the B- and T-cell epitope map of TP0136 and exploring their effect in a Treponema pallidum rabbit model.

The systemic immune response, including B- and T-cell reactions, plays a corresponding role in syphilis infections. The TP0136 protein is a target of the immune response in infected hosts and may mediate the immune response. Here, we developed a method that combining reverse vaccine approach with Pepscan/T-cell proliferation to screen and identify three B-cell and two T-cell epitopes of TP0136, and explore the role of the B- and T-cell epitopes in immunized-infected animals. The results showed that immunized with B-cell epitopes not only had no protective effect but also aggravated the syphilitic lesion development. While immunized with T-cell epitopes of TP0136 could induce a strong Th1-cellular immunity response, which could attenuate syphilitic lesion development to a certain extent. The variation in exacerbation or attenuation of skin lesions, induced by distinct B- and T-cell epitopes of Tp0136, within the host's defense against syphilis warrants in-depth exploration.

Transfusion transmissible infections among blood donors in Ghana: A 3-year multicentered health facility-based retrospective study.

Transfusion transmissible infections (TTIs) remain a major health challenge particularly in developing countries. Here, we present a multicentered hospital-based retrospective study on the prevalence, distribution, and risk factors of TTIs in Ghana. Data on blood donors from four health facilities, namely Nkwanta South Municipal Hospital (Oti region), Weija-Gbawe Municipal Hospital (Greater Accra region), SDA Hospital (Northern region) and Wa Municipal Hospital (Upper West region) were extracted and analyzed. Descriptive statistics and multinomial logistic regression were applied to compare sociodemographic data with TTI status. A total of 6094 blood donors were included in this study, and 2% were females. The overall prevalence of TTIs was 21.0% (1232/5868). Specifically, the prevalence of HBV, HCV, HIV, and Syphilis was 6.6% (385/5868), 4.9% (286/5830), 2.9% (168/5867), and 6.8% (393/5739), respectively. Wa dominated in all the viral agents considered in this study, while the Oti region recorded the highest prevalence in T. pallidum. The odds of HBV infection was 3.1 (p = 0.008) among first-time donors, while that for HCV was 2.8 (p = 0.042). For rural dwellers, donors significantly had T. pallidum (p < 0.001; OR = 2.8), HCV (p < 0.001; OR = 2.9), and HIV (p = 0.028; OR = 1.5) infections. Generally, the recipients of transfused blood were predominantly pregnant mothers, followed by children and accident victims. This study has revealed significant disparities and relatively high prevalence of TTIs in Ghana, specifically HBV, HCV, HIV and T. pallidum infections. The variations suggest the presence of unique health challenges per study area, hence the need for a tailored intervention for each study site.

Syphilis: A Modern Resurgence.

Syphilis is an important public health problem in the U.S. and many high-income nations. The rates of syphilis continue to increase and there is an urgent need for medical providers of a variety of backgrounds to recognize this disease. In this review, we cover the key clinical findings of syphilis and provide an overview of the diagnosis and management of this disease in adults.

The Epidemiological Impact of STIs among General and Vulnerable Populations of the Amazon Region of Brazil: 30 years of Surveillance.

Sexually transmitted infections (STIs) represent a worldwide public health problem and, although many of them are curable, they continue to be neglected, especially in areas with a low human development index, such as in the northern region of Brazil. This review describes the results of 30 years of studies at the Virus Laboratory at the Federal University of Pará, including the prevalence and molecular epidemiology of HIV-1, HTLV-1/2, HPV, HBV, Treponema pallidum and Chlamydia trachomatis among urban and non-urban populations, and also in vulnerable groups in the Brazilian Amazon. Control strategies and challenges in preventing STIs are discussed considering this immense geographic region, where essential health services are unable to reach the entire population, especially the most vulnerable, such as female sex workers, people who use illicit drugs, remnants of quilombolos and indigenous communities.

Seroprevalence of the Serological Markers of Transfusion-Transmissible Infections among Volunteer Blood Donors of Kosti Obstetrics and Gynecology Hospital.

BACKGROUND: Transfusion-transmissible infections are well-known global health challenges. The present study is proposed to investigate the seropositivity of anti-HIV1/2, anti-HCV, HBsAg, and anti-T.pallidum among volunteer blood donors of Kosti Obstetrics and Gynecology Hospital. METHODS: Our study was conducted in a cross-sectional retrospective manner. The data of donors who attended Kosti Obstetrics and Gynecology Hospital throughout 2016 to 2018 were reviewed and retrieved manually from blood bank records. RESULTS: Out of 8139 donors, 22.52% were seropositive for serological markers of TTIs and 1.67% were seropositive for at least two serological markers of TTIs. The overall seropositivity rate of anti-HIV1/2, HBsAg, anti-HCV, and anti-T.pallidum was 1.77%, 6.07%, 1.14%, and 11.87%, respectively (p < 0.000). Anti-T.pallidum was the most frequently detected (p < 0.05) marker across all study variables. TTIs seroprevalence was significantly (p < 0.05) varied according to the age, residence, occupations, and blood groups. Notably, there was a rising trend in the rate of anti-HIV1/2 and seropositivity for more than one marker with age (p < 0.000). Regionally, rural area residents had a higher rate of anti-HIV1/2 (2.20%), HBsAg (6.31%), anti-HCV (1.42%), anti-T.pallidum (18.38%), and multiple markers seropositivity (2.28%) compared to urban areas. Between occupations, the highest rate of anti-HIV1/2 (p = 0.483), HBsAg (p = 0.003), anti-HCV (p = 0.408), anti-T.pallidum (p < 0.000), and multiple markers seropositivity (p < 0.000) were detected in farmers. Regarding the screening, we also found that the frequency of anti-T.pallidum was significantly (p = 0.003) higher in donors who carry the AB+ve blood group, whereas anti-HCV (1.83%) was more frequent in donors carry O-ve blood group (p = 0.255). As seen, anti-T.pallidum+HBsAg was the most frequently (1.22%) co-occurring markers. In contrast, anti-T.pallidum+anti-HIV1/2+HBsAg was the lowest frequency one (p < 0.000). CONCLUSIONS: The study showed an alarming rate of TTIs, which suggests the requirement for comprehensive surveillance and health education programs.

Effect of anti-TP0136 antibodies on the progression of lesions in an infected rabbit model.

The effect of anti-TP0136 antibodies on the progression of syphilis is poorly understood. This study aimed to investigate the effect of anti-TP0136 antibodies on the progression of lesions in an infected rabbit model. Intramuscular injection of rTP0136 into rabbits in the immunized group (n = 4) elicited high titers of anti-TP0136 antibodies, and rabbits were then challenged with 105T. pallidum per site along their back. Lesion development was observed, and the injection sites were biopsied for tp0574 mRNA and histological analyses every week until the wound healed. The rabbits in the control group were injected with normal saline instead of rTP0136. Viable T. pallidum in the challenged rabbits was assessed with rabbit infectivity tests. The lesions in the immunized group took longer to heal than those in the control group (42 d vs. 28 d, P < 0.001) and had markedly higher levels of total cellular infiltrates. The mRNA level of tp0574 in the immunized group was significantly higher than that in the control group (P < 0.05). Viable T. pallidum was detected in rabbit lymph nodes in both the immunized and control groups. Our study showed that high titers of anti-TP0136 antibodies promoted the infiltration of inflammatory cells into local lesions and intensified tissue damage, thus delaying wound healing, and had no protective effect on the occurrence of syphilis in the rabbit model.

Estimation of Full-Length TprK Diversity in Treponema pallidum subsp. pallidum.

Immune evasion and disease progression of Treponema pallidum subsp. pallidum are associated with sequence diversity in the hypervariable outer membrane protein TprK. Previous attempts to study variation within TprK have sequenced at depths insufficient to fully appreciate the hypervariable nature of the protein, failed to establish linkage between the protein's seven variable regions, or were conducted on isolates passed through rabbits. As a consequence, a complete profile of tprK during infection in the human host is still lacking. Furthermore, prior studies examining how T. pallidum subsp. pallidum uses its repertoire of genomic donor sites to generate diversity within the variable regions of the tprK have yielded a partial understanding of this process due to the limited number of tprK alleles examined. In this study, we used short- and long-read deep sequencing to directly characterize full-length tprK alleles from T. pallidum subsp. pallidum collected from early lesions of patients attending two sexually transmitted infection clinics in Italy. We demonstrate that strains collected from cases of secondary syphilis contain significantly more unique variable region sequences and full-length TprK sequences than those from cases of primary syphilis. Our data, combined with recent data available on Chinese T. pallidum subsp. pallidum specimens, show the near-complete absence of overlap in TprK sequences among the 41 specimens profiled to date. We further estimate that the potential antigenic variability carried by TprK rivals that of current estimates of the human adaptive immune system. These data underscore the immunoevasive ability of TprK that allows T. pallidum subsp. pallidum to establish lifelong infection.IMPORTANCE Syphilis continues to be a significant public health issue in both low- and high-income countries, including the United States where the rate of syphilis infection has increased over the past 5 years. Treponema pallidum subsp. pallidum, the causative agent of syphilis, carries the outer membrane protein TprK that undergoes segmental gene conversion to constantly create new sequences. We performed full-length deep sequencing of TprK to examine TprK diversity in clinical T. pallidum subsp. pallidum strains. We then combined our results with data from all samples for which TprK deep sequencing results were available. We found almost no overlap in TprK sequences between different patients. Moreover, our data allowed us to estimate the total number of TprK variants that T. pallidum subsp. pallidum can potentially generate. Our results support how the T. pallidum subsp. pallidum TprK antigenic variation system is an equal adversary of the human immune system leading to pathogen persistence in the host.

Genetics of human and animal uncultivable treponemal pathogens.

Treponema pallidum is an uncultivable bacterium and the causative agent of syphilis (subsp. pallidum [TPA]), human yaws (subsp. pertenue [TPE]), and bejel (subsp. endemicum). Several species of nonhuman primates in Africa are infected by treponemes genetically undistinguishable from known human TPE strains. Besides Treponema pallidum, the equally uncultivable Treponema carateum causes pinta in humans. In lagomorphs, Treponema paraluisleporidarum ecovar Cuniculus and ecovar Lepus are the causative agents of rabbit and hare syphilis, respectively. All uncultivable pathogenic treponemes harbor a relatively small chromosome (1.1334-1.1405 Mbp) and show gene synteny with minimal genetic differences (>98% identity at the DNA level) between subspecies and species. While uncultivable pathogenic treponemes contain a highly conserved core genome, there are a number of highly variable and/or recombinant chromosomal loci. This is also reflected in the occurrence of intrastrain heterogeneity (genetic diversity within an infecting bacterial population). Molecular differences at several different chromosomal loci identified among TPA strains or isolates have been used for molecular typing and the epidemiological characterization of syphilis isolates. This review summarizes genome structure of uncultivable pathogenic treponemes including genetically variable regions.