Cerebrospinal fluid CXCL13 concentration for diagnosis of neurosyphilis: a systematic review and meta-analysis.

OBJECTIVE: To systematically assess the diagnostic accuracy of CXCL13 testing of cerebrospinal fluid (CSF) for neurosyphilis diagnosing. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Library and Web of Science databases from their inception until 1 May 2023. ELIGIBILITY CRITERIA: Both cross-sectional and case-control diagnostic test studies evaluating the diagnostic value of CSF CXCL13 in diagnosing neurosyphilis were included, with no language restrictions. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data independently from all finally included articles. The updated Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. Quantitative synthesis was done using a bivariate random-effects model. RESULTS: This meta-analysis included seven eligible studies involving a total of 1152 patients with syphilis and 430 patients with neurosyphilis. The pooled sensitivity, specificity and summary area under the curve (AUC) of CSF CXCL13 testing for the diagnosis of neurosyphilis were 0.76 (95% CI 0.64 to 0.85; I2=82%), 0.83 (95% CI 0.80 to 0.85; I2=32.29%) and 0.84 (95% CI 0.81 to 0.87), respectively. Sensitivity analysis confirmed the stability of the combined results. Meta-regression analysis revealed that the heterogeneity of pooled sensitivity was related to different study regions; subgroup analysis indicated that the diagnostic value of CSF CXCL13 testing reported in studies from China was superior to that reported in non-Chinese studies (pooled sensitivity, specificity and summary AUC values were 0.84 (I2=0) vs 0.64 (I2=79.53%), 0.83 (I2=42.03%) vs 0.83 (I2=32.87%) and 0.87 vs 0.83, respectively). The diagnostic value reported in studies with a sample size ≥200, unclassified neurosyphilis and HIV-negative subgroups was superior to the total combined value. CONCLUSIONS: This meta-analysis has demonstrated a reasonable level of accuracy for diagnosis of neurosyphilis with CSF CXCL13 testing. Further multicentre, prospective diagnostic studies, especially in asymptomatic neurosyphilis and HIV-infected patients, are needed to provide more evidence for evaluation before clinical application. PROSPERO REGISTRATION NUMBER: CRD42023414212.

Evaluation of between-assay consistency among laboratory testing methods for neurosyphilis: a systematic review.

We conducted a systematic review to analyse the consistency of nontreponemal-specific tests of Treponema pallidum in cerebrospinal fluid. We searched the PubMed, EMBASE, Web of Science, CNKI, Wanfang and Chongqing VIP databases. The inclusion criteria were studies conducted on nontreponemal-specific tests in cerebrospinal fluid (CSF) within the same population. Exclusion criteria were studies with incomplete data or where we were unable to obtain the full text, duplicate reports, case reports and studies without sensitivity or specificity results. We used kappa value analysis and McNemar's test to analyse study consistency. We initially collected a total of 198 articles and ultimately included six articles that involved 429 patients with neurosyphilis. The performance between venereal disease research laboratory tests (VDRL) and the reactive plasma regain or toluidine red serum unheated test was similar. The kappa value for consistency between VDRL and reactive plasma regain was >0.8 in three articles, and was 0.892 for consistency between VDRL and toluidine red serum unheated test in one article. Our results suggested that CSF-reactive plasma regain or CSF-toluidine red serum unheated test may serve as alternative tests in the diagnosis of neurosyphilis with CSF-VDRL.

Awareness and willingness to accept syphilis chemoprophylaxis among men who have sex with men from three cities in China: a cross-sectional study.

BACKGROUND: The awareness and willingness to use doxycycline-based syphilis chemoprophylaxis among men who have sex with men (MSM) in China remain largely unknown. METHODS: We recruited MSM online from Nanjing, Wuhan and Changsha between August and October of 2021, collected data from online survey, analyzed their data using descriptive statistics, and constructed binary logistic regression for factors associated with awareness and willingness to use chemoprophylaxis for syphilis and HIV. RESULTS: Of 725 participants (44.0% of which resided in Nanjing, 37.7% in Changsha, and 18.3% in Wuhan), a majority were under 25 years of age; 62.2% had college degrees; 11.3% were HIV positive; and 5.10% had prior syphilis infection. Only 28.83% of participants had heard of syphilis chemoprophylaxis before. Odds of knowing syphilis chemoprophylaxis were higher in those who think it is necessary to have syphilis chemoprophylaxis versus those who think it is unnecessary (P = 0.002), and were higher in those whose acquaintance had chemoprophylaxis experience before (P < 0.001). Meanwhile, those who had no previous doxycycline using history, or had positive attitude were more likely to be willing to accept syphilis chemoprophylaxis (P = 0.009, P < 0.001). Over two-thirds (67.8%) of participants preferred the PEP mode in syphilis chemoprophylaxis, and side-effects of drugs remains their most worrying aspect. CONCLUSIONS: We observed elevated interest in syphilis chemoprophylaxis in MSM in our investigational areas, indicating that the combination of HIV and syphilis chemoprophylaxis in China is promising.

Ceftriaxone compared with penicillin G for the treatment of neurosyphilis: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Neurosyphilis may cause irreversible neurological sequelae. First-line treatment consists of penicillin G, with ceftriaxone being an alternative treatment in patients allergic to penicillin. The lack of clinical data comparing the efficacy of these two drugs indicated the need for comparative clinical trials to improve national treatment guidelines in China. METHODS/DESIGN: In this multicenter randomized controlled clinical trial, 290 patients newly diagnosed with neurosyphilis will be randomized 1:1 to treatment with aqueous crystalline penicillin G (ACPG) or ceftriaxone. Patients will be treated with standard regimens of ACPG or ceftriaxone according to Chinese National Guidelines and will be followed up for 12 months. All clinical parameters will be assessed at baseline and at follow-up 3, 6, 9, and 12 months later. The primary outcomes will include cerebrospinal fluid (CSF) white blood cell (WBC) count, serological efficacy, and clinical efficacy. The secondary outcomes will include CSF protein concentrations, Mini-Mental State Examination (MMSE) scores, imaging results, recurrence, and time to recovery from neurosyphilis. Adverse events will be monitored and recorded during the trial. DISCUSSION: This trial will provide clinical data to determine whether ceftriaxone is non inferior to ACPG in treating neurosyphilis and will provide evidence for the improvement of treatment guidelines. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100047164. Registered on 9 June 2021 and updated on 23 November 2021.

High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny.

Sequencing of most Treponema pallidum genomes excludes repeat regions in tp0470 and the tp0433 gene, encoding the acidic repeat protein (arp). As a first step to understanding the evolution and function of these genes and the proteins they encode, we developed a protocol to nanopore sequence tp0470 and arp genes from 212 clinical samples collected from ten countries on six continents. Both tp0470 and arp repeat structures recapitulate the whole genome phylogeny, with subclade-specific patterns emerging. The number of tp0470 repeats is on average appears to be higher in Nichols-like clade strains than in SS14-like clade strains. Consistent with previous studies, we found that 14-repeat arp sequences predominate across both major clades, but the combination and order of repeat type varies among subclades, with many arp sequence variants limited to a single subclade. Although strains that were closely related by whole genome sequencing frequently had the same arp repeat length, this was not always the case. Structural modeling of TP0470 suggested that the eight residue repeats form an extended α-helix, predicted to be periplasmic. Modeling of the ARP revealed a C-terminal sporulation-related repeat (SPOR) domain, predicted to bind denuded peptidoglycan, with repeat regions possibly incorporated into a highly charged ß-sheet. Outside of the repeats, all TP0470 and ARP amino acid sequences were identical. Together, our data, along with functional considerations, suggests that both TP0470 and ARP proteins may be involved in T. pallidum cell envelope remodeling and homeostasis, with their highly plastic repeat regions playing as-yet-undetermined roles.

Neurosyphilis in China: A Systematic Review of Cases From 2009-2021.

Considered the increased threaten of neurosyphilis in China, a review on cases reported in the literature to describe the clinical epidemiological characteristics of neurosyphilis cases, may be beneficial to the early detection and management strategies of neurosyphilis for clinicians. We searched the literature on Chinese neurosyphilis cases published from January 1, 2009 to December 31, 2021, described their clinical epidemiological characteristics and calculated the prevalence of neurosyphilis amongst other associated diseases, according to the individual study criteria. A total of 284 studies including 7,486 neurosyphilis cases were included. No meta-analysis was performed due to the heterogeneity of the data. Among 149 case reports and 93 retrospective case series studies, the main clinical manifestation of 3,507 neurosyphilis cases was cerebral parenchymal syphilis (57.3%), followed by asymptomatic neurosyphilis (16.7%), meningovascular syphilis (13.6%), meningitis syphilis (7.7%) and ocular syphilis (2.8%), etc. In addition, the initial diagnosis was incorrect in 53.2% patients, and the most frequent misdiagnoses were mental disorders (31.0%), stroke (15.9%), cognitive impairment (9.0%), etc. The positive or abnormal rates of cerebrospinal fluid non-treponemal and treponemal tests, white blood cell counts and protein concentrations were 74.2%, 96.2%, 61.5%, and 60.9%, respectively. Aqueous penicillin was the first choice for treatment in 88.3% cases, and 81.7% and 50.0% patients had response in the improvement of symptoms and serological effective in CSF, respectively. Among 26 studies on neurosyphilis patients amongst other associated diseases, the prevalence of neurosyphilis amongst central nervous system infectious diseases, syphilis-associated neurological symptoms, serofast status, coinfected with human immunodeficiency virus were 10.6%-30.1%, 23.2%-35.5%, 9.8%-56.1%, and 8.9%, respectively. In summary, the lack of early detection of neurosyphilis cases remains a clinical challenge. The high rate of misdiagnosis and high prevalence of neurosyphilis amongst associated diseases strongly remind clinicians to focus on the early detection among suspected cases. Besides, the standard treatment regimen and long-term follow-up, which complied with guideline should be provided. Further prospective studies are urgent to better delineate the clinical epidemiological characteristics of neurosyphilis in China.

Eliminating Mother-to-Child Transmission of Syphilis: Chinese Practice before and during COVID-19 Pandemics.

Mother-to-child transmission (MTCT) of syphilis remains a leading cause of stillbirth and death among neonates in many developing countries. In 2007, WHO launched the global elimination of MTCT (EMTCT) of syphilis. Given the high burden of congenital syphilis, China subsequently released the specific national EMTCT policies and programs to reduce MTCT of syphilis. The congenital syphilis incidence rate per 100 000 live births in China has markedly decreased from 69.9 in 2013 to 11.9 in 2019. However, due to the global pandemic of COVID-19, the current measures for eliminating MTCT of syphilis are great challenged. In this article, we summarize the strategies and measures for the EMTCT of syphilis in China in the past 20 years, point out that we have made remarkable achievements due to the national health policy support and strong leadership of the government. In the context of COVID-19 pandemics, strengthening emergency response to the regional outbreaks of COVID-19 and adopting safe, rapid, early and high-quality clinical care to ensure that 100% of pregnant women receive prenatal syphilis testing services, ensuring the availability of Benzathine penicillin for the treatment, and strengthening the closed-loop management of pregnant women and newborns infected with syphilis are key measures to determine the effect of MTCT of syphilis. Lessons from China may be valuable for other countries that are planning to eliminate MTCT of syphilis.

CARE-NS, a research strategy for neurosyphilis.

Neurosyphilis is a major clinical manifestation of syphilis. In recent years, an increase in neurosyphilis cases has been reported in many countries. The overall incidence of neurosyphilis remains unknown, and there is a lack of understanding of the disease pathogenesis, which hampers clinical management, development of prevention strategies, and control. This article proposes the CARE-NS research strategy to enhance the clinical management of neurosyphilis, which consists of six key features: comprehensive management including multidisciplinary treatment (C), alleviating neurological impairment and sequelae (A), risk factors and clinical epidemiology (R), etiology and pathogenesis (E), new diagnostic indicators and strategies (N), and social impact and cost-effectiveness analysis (S).

Treponema pallidum genome sequencing from six continents reveals variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar.

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 challenge of diagnosis and treatment of neurosyphilis in China: results from a nationwide survey.

Background The uncertainty of how neurosyphilis is diagnosed and treated in clinical settings led us to investigate whether this serious manifestation of syphilis infection is properly managed in China. METHODS: This national cross-sectional study of the diagnosis and treatment of neurosyphilis included 1392 clinicians at 398 hospitals located in 116 cities in China. RESULTS: Of 398 hospitals, 244 (61.3%) failed to perform diagnostic laboratory tests and 181 (45.5%) failed to provide recommended treatment for neurosyphilis. Of 1392 clinicians, 536 (38.5%) had previously diagnosed patients with neurosyphilis, but 419 (78.2%) of the latter provided diagnoses that did not meet the criteria set by national guidelines. Of the 485 clinicians who had previously treated patients with neurosyphilis, 280 (57.7%) failed to follow national guidelines for treatment. Analysis indicated that clinicians working in North China (adjusted odds ratio (aOR), 4.24; 95% confidence interval (CI), 1.65-10.88), tertiary hospitals (aOR, 3.23; 95% CI, 1.63-6.41), and hospitals specialising in sexually transmitted infections (aOR, 2.49; 95% CI, 1.24-4.99) were more likely to follow national guidelines for neurosyphilis treatment. CONCLUSION: Lack of knowledge in disease management poses a great obstacle to prevent the serious consequences of neurosyphilis in Chinese patients. More effective measures are urgently needed to improve this suboptimal situation.

A Novel tp0548 Gene Type of Treponema pallidum Identified in Nanjing, China: Case Report and Review of Literature.

BACKGROUND: The tp0548 gene, hypothesized to encode for an outer-membrane protein, was originally used in the enhanced Centers for Disease Control and Prevention typing for molecular typing of Treponema pallidum. It plays an important role in the molecular epidemiology of Treponema because it is not only an important locus of multiple typing approaches but also suitable for strain typing of multiple Treponema subspecies. METHODS: A 27-year-old Chinese man attended the Institute of Dermatology, Chinese Academy of Medical Sciences Sexually Transmitted Disease Clinic in Nanjing, China, because of a genital ulcer and inguinal lymphadenopathy for 1 week. Workup consisted of microbiological and hematological investigations, and sequences analysis. The aims of this study were to describe a novel tp0548 sequence type "Qn" of this syphilis strain and to review all previously reported novel tp0548 genotypes. RESULTS: We identified a novel tp0548 gene type in a genital ulcer in a patient with primary syphilis in Nanjing, China. Using sequence alignment, we further found that this novel sequence was closely similar to "Q." Following the nomenclature used in the enhanced Centers for Disease Control and Prevention typing methodology, the letters "Qn" was assigned to the new sequence type. CONCLUSION: The novel tp0548 sequence type of T. pallidum not only expands the database up to 27 different sequence types but also indicates the substantial genetic diversity of the tp0548 gene sequence.

MiR-223-3p inhibits rTp17-induced inflammasome activation and pyroptosis by targeting NLRP3.

The incidence of syphilis caused by Treponema pallidum subsp pallidum (T pallidum) infection is accompanied by inflammatory injuries of vascular endothelial cells. Studies have revealed that T pallidum infection could induce inflammasome activation and pyroptosis in macrophages. MicroRNA-223-3p (miR-223-3p) was reported to be a negative regulator in inflammatory diseases. The present study aimed to explore whether miR-223-3p regulates T pallidum-induced inflammasome activation and pyroptosis in vascular endothelial cells, and determine the mechanisms which underlie this process. MiR-223-3p levels in syphilis and control samples were determined. The biological function of miR-223-3p in the NLRP3 inflammasome and pyroptosis was evaluated in T pallidum-infected human umbilical vein endothelial cells (HUVECs). We observed a dramatic decrease in miR-223-3p levels in syphilis patients (n = 20) when compared to healthy controls (n = 20). Moreover, miR-223-3p showed a notable inhibitory effect on recombinant Tp17 (rTP17)-induced caspase-1 activation, resulting in decrease in IL-1ß production and pyroptosis, which was accompanied by the release of lactate dehydrogenase (LDH) in HUVECs. Additionally, the dual-luciferase assay confirmed that NLRP3 is a direct target of miR-223-3p. Moreover, NLRP3 overexpression or knockdown largely blocked the effects of miR-223-3p on T pallidum-induced inflammasome activation and pyroptosis in HUVECs. Most importantly, a notable negative correlation was observed between miR-223-3p and NLRP3, caspase-1, and IL-1ß, respectively, in the serum of syphilis patients and healthy controls. Taken together, our results reveal that miR-223-3p targets NLRP3 to suppress inflammasome activation and pyroptosis in T pallidum-infected endothelial cells, implying that miR-223-3p could be a potential target for syphilis patients.

The Treponema pallidum outer membrane protein Tp92 activates endothelial cells via the chemerin/CMKLR1 pathway.

Endothelium damage caused by Treponema pallidum is the key step in the systemic dissemination and pathophysiology of syphilis, particularly cardiovascular syphilis and neurosyphilis. However, the molecular mechanisms supporting endothelium damage of syphilis are undefined. The outer membrane proteins were thought to be involved. Tp92 was first identified as an outer membrane protein of T. pallidum. Homologous proteins to Tp92 play important roles in cell attachment, inflammation, and tissue destruction in other bacterial species. In this study, we investigated the effect of Tp92 on endothelial cells activation. The data showed that Tp92 induced chemerin production in activated endothelial cells. Endothelial cell-derived chemerin upregulated the expression of TNF-α and ICAM-1 in endothelial cells via CMKLR1. In addition, endothelial cell-derived chemerin promoted THP-1-derived macrophage migration towards endothelial cells. These findings suggest that Tp92 may play an important role in mediating endothelial cell activation by inducing the secretion of chemerin.

Chemerin induced by Treponema pallidum predicted membrane protein Tp0965 mediates the activation of endothelial cell via MAPK signaling pathway.

Chemerin, a chemoattractant protein, is involved in endothelial dysfunction and vascular inflammation in pathological conditions. In a recent study, we observed the upregulation of chemerin in endothelial cells following in vitro treatment with Treponema pallidum. Here, we investigated the role of chemerin in endothelial cells activation induced by the T. pallidum predicted membrane protein Tp0965. Following stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, chemerin and its receptor chemerin receptor 23 (ChemR23) were upregulated, companied with elevated expression of Toll-like receptor 2. Furthermore, chemerin from HUVECs activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by upregulated expression of intercellular adhesion molecule 1, E-selectin, and matrix metalloproteinase-2. Activation of endothelial cells depended on the mitogen-activated protein kinase signaling pathway. In addition, Tp0965-induced chemerin promoted THP-1-derived macrophages migration to endothelial cells, also via the chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved in THP-1-derived macrophages migration in response to chemerin/ChemR23. Our results highlight the role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to the immunopathogenesis of vascular inflammation of syphilis.

Treponema pallidum induces the activation of endothelial cells via macrophage-derived exosomes.

Recent studies have shown that exosomes play a role in pathogenesis and in the treatment of inflammatory diseases and tumours. We explored the effects of Treponema pallidum-induced macrophage-derived exosomes on vascular endothelial cells to determine whether they are involved in the pathogenesis of syphilis. A syphilis infection model was established using rabbits to harvest T. pallidum at the peak of proliferation. Exosomes derived from macrophages were extracted using commercial kits and characterized by transmission electron microscopy, western blot assays, and nanoparticle tracking analysis. Secreted cytokine levels and the adhesion and permeability of human umbilical vein endothelial cells were evaluated in a co-culture model using the extracted exosomes. The results of this study revealed that exosomes derived from T. pallidum-infected macrophages enhanced cell adhesion and permeability. The levels of the secreted cytokines, including ICAM-1, VCAM-1, VEGF, and IL-8 were higher in the experimental group than in the control group. Our findings suggest that exosomes derived from T. pallidum-infected macrophages affect the cell adhesion and permeability of vascular endothelial cells. These changes may play important roles in syphilis pathogenesis. This study is the first to reveal the effects of exosomes derived from T. pallidum-infected macrophages on the adhesion, permeability, and secreted cytokines of human umbilical vein endothelial cells.

Evaluation of IL-17A, IL-17F, IL-23R, VDR, CCL2, CCL5, CCR2, and CCR5 gene polymorphisms and expression in Chinese individuals with syphilis.

Syphilis is a sexually transmitted disease caused by the infection of Treponema pallidum subspecies pallidum. T-helper type 17-related genes, vitamin D receptor (VDR) gene, and chemokine/chemokine receptor genes are crucial in microbial infection. A total of 16 single-nucleotide polymorphisms (SNPs) in eight genes (interleukin [IL]-17A, IL-17F, IL-23R, VDR, C-C motif chemokine ligand [CCL] 2, CCL5, C-C chemokine receptor [CCR] 2, and CCR5) were analyzed in 188 patients with syphilis and 216 healthy controls. The results showed a strong correlation of IL-17A rs2275913 (AA vs AG + GG: odds ratio [OR], 1.78; 95% confidence interval [CI], 1.09 to 2.92; P = 0.020; A vs G: OR, 1.33; 95% CI, 1.01 to 1.76; P = 0.043) and rs3819024 (GG vs AA + GA: OR, 1.76; 95% CI, 1.06 to 2.91; P = 0.028; G vs A: OR, 1.36; 95% CI, 1.03 to 1.80; P = 0.030) with syphilis. In haplotype analysis, IL-17A rs2275913A/rs3819024G showed a risk effect (OR, 1.38; 95% CI, 1.04 to 1.82; P = 0.026), whereas IL-17A rs2275913G/rs3819024A showed a protective effect (OR, 0.76; 95% CI, 0.57 to 0.998; P = 0.048). The expression levels of IL-17A messenger RNA (mRNA) in peripheral blood mononuclear cells and IL-17A secretion in plasma were further examined. No significant differences were found between patients with syphilis and healthy controls. The study also explored whether IL-17A rs2275913 and rs3819024 were associated with the expression of IL-17A mRNA and IL-17A secretion in patients with syphilis. Similar negative results were found. In conclusion, the polymorphisms of IL-17A rs2275913 and rs3819024 and the haplotype containing these two SNPs influenced the susceptibility to syphilis in a Han Chinese population.

Molecular subtyping of Treponema pallidum and associated factors of serofast status in early syphilis patients: Identified novel genotype and cytokine marker.

Serofast, a persistent nontreponemal serological response observed in early syphilis patients after conventional treatment, remains a concern of clinicians and syphilis patients. No consensus has been established, however, that defines an effective treatment strategy and clarifies the pathogenesis. In this study, 517 patients with early syphilis were enrolled and treated. Twelve months after treatment, 79.3% (410/517) of patients achieved serological cure, 20.1% (104/517) were serofast, and 0.6% (3/517) were serological failures. Multivariate analysis demonstrated that older age (>40 years) and lower baseline RPR titer (≤ 1:8) were associated with serofast status. We also identified 21 T. pallidum molecular subtypes among early syphilis patients and detected a new subtype, 14i/a. We found that the proportion of 14i/a type in serofast patients was significantly higher than that in patients with serological cure, predicting an increasing risk of serofast status. Levels of chemerin were higher in the serum of serofast cases than serological cure cases, potentially indicating a novel cytokine marker for serofast in early syphilis patients after therapy. We hope that these results contribute to improve guidelines for the management of syphilis patients who experience serofast.

Tp17 membrane protein of Treponema pallidum activates endothelial cells in vitro.

Tp17, a membrane immunogen of Treponema pallidum subsp. pallidum, was initially recognized as an inflammatory mediator of syphilis. Because the histopathology of syphilis is characterized by endothelial cell abnormalities, we investigated the effects of recombinant Tp17 (rTp17) on endothelial cell activation in vitro. Using real-time reverse transcription-PCR and whole-cell ELISA, we found that rTp17 activated endothelial cells, as demonstrated by the up-regulated expression and increased gene transcription of intercellular adhesion molecule 1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1). rTp17 also enhanced the migration and subsequent adhesion of monocytes to endothelial cells as well as increased transendothelial migration of monocytes. These data suggest that the ability of Tp17 to activate endothelial cells may play an important role in the immunopathogenesis of syphilis.

Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer.

The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.