A novel syphilis Treponema pallidum lipoprotein peptide antigen diagnostic assay using red cell kodecytes in routine blood centre column agglutination testing platforms.

BACKGROUND AND OBJECTIVES: The detection of treponemal antibodies, which are used to make a diagnosis of syphilis, is important both for diagnostic purposes and as a mandatory blood donor test in most countries. We evaluated the feasibility of using Kode Technology to make syphilis peptide red cell kodecytes for use in column agglutination serologic platforms. MATERIALS AND METHODS: Candidate Kode Technology function-spacer-lipid (FSL) constructs were made for the Treponema pallidum lipoprotein (TmpA) of T. pallidum, using the peptide and FSL selection algorithms, and then used to make kodecytes. Developmental kodecytes were evaluated against a large range of syphilis antibody reactive and non-reactive samples in column agglutination platforms and compared against established methodologies. Overall, 150 reactive and 2072 non-reactive Syphicheck assay (a modified T. pallidum particle agglutination) blood donor samples were used to evaluate the agreement rate of the developed kodecyte assay. RESULTS: From three FSL-peptide candidate constructs, one was found to be the most suitable for diagnostics. Of 150 Syphicheck assay reactive samples, 146 were TmpA-kodecyte reactive (97.3% agreement), compared with 58.0% with the rapid plasmin reagin (RPR) assay for the same samples. Against the 2072 expected syphilis non-reactive samples the agreement rate for TmpA-kodecytes was 98.8%. CONCLUSION: TmpA-kodecytes are viable for use as cost-effective serologic reagent red cells for the detection of treponemal antibodies to diagnose syphilis with a high level of specificity in blood centres. This kodecyte methodology also potentially allows for introduction of the reverse-algorithm testing into low-volume laboratories, by utilizing existing transfusion laboratory infrastructure.

Neurosyphilis Presenting as Psychiatric Symptoms at Younger Age: A Case Report.

Neurosyphilis is a central nervous system infection caused by Treponema pallidum that imitates various neurological and mental disorders. Therefore, patients with this disease are prone to misdiagnoses. Here, we report a case of neurosyphilis with a psychotic disorder as the main manifestation. A young girl exhibited mental and behavioural abnormalities after a heartbreak, which manifested as alternating low mood, emotional irritability, and a lack of interest in social relations, followed by memory loss. The cerebrospinal fluid protein - Treponema pallidum particle agglutination test was positive, the toluidine red unheated serum test titre was 1:4, the white blood cell count was 5 × 10^6/L, the cerebrospinal fluid protein level was 0.97 g/L, and the brain CT was abnormal. After admission, the possibility of neurosyphilis was considered and the patient received intravenous penicillin G treatment. The patient's clinical symptom ms improved. This case emphasises that doctors should maintain clinical suspicion of Treponema pallidum infection in adolescent patients with mental abnormalities.

An Exuberant Case of Ulceronodular-Rupioid (Malignant) Syphilis in an HIV Patient: A Proposal for New Diagnostic Criteria.

We report the case of a 28-year-old male with uncontrolled human immunodeficiency virus (HIV) infection who presented with extensive ulcerated lesions with dark lamellated crusting on his face, torso, and limbs. The patient had a rapid plasma reagin (RPR) titer of 1:512, indicative of syphilis. A skin biopsy revealed granulomata surrounded by lymphocytes, histiocytes, and plasma cells, with spirochetes visible on immunohistochemical staining. The patient's rash resolved with hyperpigmented scarring after penicillin and doxycycline treatment. This severe form of secondary syphilis has been termed malignant syphilis, lues maligna, ulceronodular syphilis, or rupioid syphilis. We propose a single descriptive name for this entity, ulceronodular-rupioid syphilis. In 1969, Fisher proposed criteria for malignant syphilis based on lesion appearance, histopathologic findings, high RPR values, and rapid response to treatment. We found that the Fisher criteria were imprecise with respect to specific histopathologic findings, the quantitation of RPR values, and what constitutes rapid response to treatment. Thus, we examined an additional 74 cases from the literature and propose new diagnostic criteria based on rash appearance, histopathologic characteristics, non-treponemal and treponemal test positivity, and response to therapy. We also found that uncontrolled viremia, and not a low CD4 count, is a major risk factor for ulceronodular-rupioid syphilis in HIV patients.

Syphilis susceptibility factors atlas: A wide-angled Mendelian randomization study.

OBJECTIVE: The pathogenic mechanisms of syphilis and the host defense mechanisms against syphilis remain poorly understood. Exploration of the susceptibility factors of syphilis may provide crucial clues for unraveling its underlying mechanisms. METHODS: A two-sample Mendelian Randomization framework was utilized, and the inverse-variance weighted method was used as the main analysis. All data was sourced from Genome-wide association studies datasets from 2015 to 2022 in Europe, and all participants were of European descent. Only summary-level statistics were used. Sensitivity analyses were conducted to evaluate the heterogeneity and pleiotropy of the datasets. RESULTS: Our study established 18 exposure factors (12 risk factors and 6 protective factors) for syphilis susceptibility. Twelve factors encompassing body mass index, waist circumference, darker natural skin, cooked vegetable intake, processed meat intake, diabetes mellitus, glucose regulation disorders, gout, autoimmune diseases, rheumatoid arthritis, diverticulitis, and longer menstrual cycles were found to increase susceptibility to syphilis. In contrast, 6 factors including easier skin tanning, blonde natural hair color, irritability, higher neuroticism scores, extended sleep duration, and delayed age at first sexual intercourse were connected to a reduced risk of syphilis infection (all P < 0.05). CONCLUSIONS: This study identified 18 influencing factors of syphilis susceptibility. These findings offered novel insights for further probing into the underlying pathogenic mechanisms of syphilis and underscored the importance of multifaceted prevention strategies against syphilis.

Clinical presentation of early syphilis and genomic sequences of Treponema pallidum strains in patient specimens and isolates obtained by rabbit inoculation.

BACKGROUND: The global resurgence of syphilis necessitates vaccine development. METHODS: We collected ulcer exudates and blood from 17 primary syphilis (PS) participants and skin biopsies and blood from 51 secondary syphilis (SS) participants in Guangzhou, China for Treponema pallidum subsp. pallidum (TPA) qPCR, whole genome sequencing (WGS), and isolation of TPA in rabbits. RESULTS: TPA DNA was detected in 15 of 17 ulcer exudates and 3 of 17 blood PS specimens. TPA DNA was detected in 50 of 51 SS skin biopsies and 27 of 51 blood specimens. TPA was isolated from 47 rabbits with success rates of 71% (12/17) and 69% (35/51), respectively, from ulcer exudates and SS bloods. We obtained paired genomic sequences from 24 clinical samples and corresponding rabbit isolates. Six SS14- and two Nichols-clade genome pairs contained rare discordances. Forty-one of the 51 unique TPA genomes clustered within SS14 subgroups largely from East Asia, while 10 fell into Nichols C and E subgroups. CONCLUSIONS: Our TPA detection rate was high from PS ulcer exudates and SS skin biopsies and over 50% from SS blood, with TPA isolation in over two-thirds of samples. Our results support the use of WGS from rabbit isolates to inform vaccine development.

The incidence of new cases of syphilis has skyrocketed globally in the twenty-first century. This global resurgence requires new strategies, including vaccine development. As part of an NIH funded Cooperative Research Center to develop a syphilis vaccine, we established a clinical research site in Guangzhou, China to better define the local syphilis epidemic and obtain samples from patients with primary and secondary syphilis for whole genome sequencing (WGS) of circulating Treponema pallidum strains. Inoculation of rabbits enabled us to obtain T. pallidum genomic sequences from spirochetes disseminating in blood, a compartment of immense importance for syphilis pathogenesis. Collectively, our results further clarify the molecular epidemiology of syphilis in southern China, enrich our understanding of the manifestations of early syphilis, and demonstrate that the genomic sequences of spirochetes obtained by rabbit inoculation accurately represent those of the spirochetes infecting the corresponding patients.

Condyloma lata of the umbilicus: A case report highlighting the present syphilis emergency.

Syphilis is an ancient sexually transmitted infection that plagues communities across the United States and the world. Cutaneous syphilis has a wide variety of manifestations and presentations, and is notoriously difficult to identify clinically as a result. In this report, we describe the case of a 30-year-old patient with condyloma lata on the umbilicus, an extremely rare site for the presentation of these lesions. With the recent surge in syphilis infections nationwide, including congenital infections, this case underscores the urgent necessity for heightened syphilis awareness and suspicion among clinicians.

Uncovering the mechanisms of host mitochondrial cardiolipin release in syphilis: Insights from human microvascular endothelial cells.

The release of host mitochondrial cardiolipin is believed to be the main factor that contributes to the production of anti-cardiolipin antibodies in syphilis. However, the precise mechanism by which mitochondria release cardiolipin in this context remains elusive. This study aimed to elucidate the mechanisms underlying mitochondrial cardiolipin release in syphilis. We conducted a cardiolipin quantitative assay and immunofluorescence analysis to detect mitochondrial cardiolipin release in human microvascular endothelial cells (HMEC-1), with and without Treponema pallidum (Tp) infection. Furthermore, we explored apoptosis, a key mechanism for mitochondrial cardiolipin release. The potential mediator molecules were then analyzed through RNA-sequence and subsequently validated using in vitro knockout techniques mediated by CRISPR-Cas9 and pathway-specific inhibitors. Our findings confirm that live-Tp is capable of initiating the release of mitochondrial cardiolipin, whereas inactivated-Tp does not exhibit this capability. Additionally, apoptosis detection further supports the notion that the release of mitochondrial cardiolipin occurs independently of apoptosis. The RNA-sequencing results indicated that microtubule-associated protein2 (MAP2), an axonogenesis and dendrite development gene, was up-regulated in HMEC-1 treated with Tp, which was further confirmed in syphilitic lesions by immunofluorescence. Notably, genetic knockout of MAP2 inhibited Tp-induced mitochondrial cardiolipin release in HMEC-1. Mechanically, Tp-infection regulated MAP2 expression via the MEK-ERK-HES1 pathway, and MEK/ERK phosphorylation inhibitors effectively block Tp-induced mitochondrial cardiolipin release. This study demonstrated that the infection of live-Tp enhanced the expression of MAP2 via the MEK-ERK-HES1 pathway, thereby contributing to our understanding of the role of anti-cardiolipin antibodies in the diagnosis of syphilis.

Risk for Donor-Derived Syphilis after Kidney Transplantation, China, 2007-2022.

To evaluate the risk of acquiring syphilis from a donated kidney, we evaluated kidney transplantation pairs from West China Hospital, Sichuan, China, during 2007-2022. Donor-derived syphilis was rare. Risk may be higher if donors have active syphilis and may be reduced if recipients receive ceftriaxone.

Coinfection of a yaws patient with two closely related Treponema pallidum subsp. pertenue strains: A rare event with potential evolutionary implications.

The etiological agent of yaws is the spirochete Treponema pallidum (TP) subsp. pertenue (TPE) and infects the children of Papua New Guinea, causing ulcerative skin lesions that impairs normal growth and development. Closely related strains of Treponema pallidum subsp. pertenue, JE11, and TE13 were detected in an ulcer biospecimen derived from a 5-year-old yaws patient. Cloning experiments validated the presence of two distinct but similar genotypes, namely TE13 and JE11, co-occurring within a single host. While coinfection with highly related TPE strains has only limited epidemiological and clinical relevance, this is the first documented coinfection with genetically distinct TP strains in a single patient. Similar coinfections in the past were explained by the existence of over a dozen recombinant loci present in the TP genomes as a result of inter-strain or inter-subspecies recombination events following an anticipated scenario of TP coinfection, i.e., uptake of foreign DNA and DNA recombination.

Platelet-derived major histocompatibility complex class I coating on Treponema pallidum attenuates natural killer cell lethality.

The evasive tactics of Treponema pallidum pose a major challenge in combating and eradicating syphilis. Natural killer (NK) cells mediate important effector functions in the control of pathogenic infection, preferentially eliminating targets with low or no expression of major histocompatibility complex (MHC) class I. To clarify T. pallidum's mechanisms in evading NK-mediated immunosurveillance, experiments were performed to explore the cross-talk relations among T. pallidum, NK cells, and platelets. T. pallidum adhered to, activated, and promoted particle secretion of platelets. After preincubation with T. pallidum, platelets expressed and secreted high levels of MHC class I, subsequently transferring them to the surface of T. pallidum, potentially inducing an immune phenotype characterized by the "pseudo-expression" of MHC class I on the surface of T. pallidum (hereafter referred to a "pseudo-expression" of MHC class I). The polA mRNA assay showed that platelet-preincubated T. pallidum group exhibited a significantly higher copy number of polA transcript than the T. pallidum group. The survival rate of T. pallidum mirrored that of polA mRNA, indicating that preincubation of T. pallidum with platelets attenuated NK cell lethality. Platelets pseudo-expressed the MHC class I ligand on the T. pallidum surface, facilitating binding to killer cell immunoglobulin-like receptors with two immunoglobulin domains and long cytoplasmic tail 3 (KIR2DL3) on NK cells and initiating dephosphorylation of Vav1 and phosphorylation of Crk, ultimately attenuating NK cell lethality. Our findings elucidate the mechanism by which platelets transfer MHC class I to the T. pallidum surface to evade NK cell immune clearance.

Treponema pallidum recombinant protein Tp0768 enhances the ability of HUVECs to promote neutrophil chemotaxis through TLR2/ER stress signaling pathway.

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema Pallidum (T. pallidum) remains unknow. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768(also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1(C-X-C Motif Chemokine Ligand 1), CXCL2(C-X-C Motif Chemokine Ligand 2), and CXCL8(C-X-C Motif Chemokine Ligand 8, also known as interleukin-8). At the same time, the results show that Toll Like Receptor 2 (TLR2) signaling pathway is activated and endoplasmic reticulum stress (ER stress) occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Immunoglobulin-Regulated Enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress-related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection.

Hippocampal region metabolites and cognitive impairment in patients with general paresis: based on 1H-proton magnetic resonance spectroscopy.

Background: This study utilizes Hydrogen proton magnetic resonance spectroscopy (1H-MRS) to investigate metabolite concentrations in the bilateral hippocampus of general paresis (GP) patients. Methods: A total of 80 GP patients and 57 normal controls (NCs) were enrolled. Metabolite ratios in the bilateral hippocampus were measured using 1H-MRS. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on MMSE scores, participants were categorized into normal control, mild cognitive impairment, and moderate-severe dementia groups. Metabolite ratios (N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/choline (Cho), myoinositol (MI)/creatine (Cr), choline (Cho)/N-acetylaspartate (NAA)) were compared between groups, and correlations between metabolite ratios and cognitive performance were examined. Results: MMSE scores progressively decreased in the normal, mild cognitive impairment, and moderate-severe dementia groups (p < 0.001). The moderate-severe dementia group showed significantly lower NAA/Cr ratios in the left hippocampus region (L-NAA/Cr ratios) (p < 0.001) and higher Cho/NAA ratios in the left hippocampus region (L-Cho/NAA ratios) (p < 0.05) compared to the other groups. However, differences in L-NAA/Cr and L-Cho/NAA ratios between the mild cognitive impairment group and the NC group were not significant in the hippocampus region (p > 0.05). NAA/Cho and NAA/Cr ratios in the right hippocampus region (R-NAA/Cho and R-NAA/Cr ratios) in the moderate-severe dementia group were lower than those in the control group (p < 0.05). No correlation was found between metabolite ratios and MMSE scores in bilateral hippocampus regions. Conclusion: There are distinctive metabolic characteristics in the hippocampus of GP patients. GP patients exhibited lower NAA/Cr and NAA/Cho ratios in the bilateral hippocampus, indicating neuron loss in these areas, which may become more pronounced as the disease progresses.

Southern African HIV Clinicians Society Guideline for the clinical management of syphilis.

Syphilis, 'the great imitator', caused by Treponema pallidum infection, remains a complex and multifaceted disease with a rich history of clinical diversity. This guideline aims to be a comprehensive guide for healthcare workers in Southern Africa, offering practical insights into the epidemiology, pathogenesis, clinical manifestations, diagnostic testing, therapeutic principles, and public health responses to syphilis. Although the syphilis burden has declined over the years, recent data indicate a troubling resurgence, particularly among pregnant women and neonates. This guideline highlights the diagnostic challenges posed by syphilis, stemming from the absence of a single high-sensitivity and -specificity test. While treatment with penicillin remains the cornerstone of treatment, alternative regimens may be used for specific scenarios. We highlight the importance of thorough patient follow-up and management of sex partners to ensure optimal care of syphilis cases. In the context of public health, we emphasise the need for concerted efforts to combat the increasing burden of syphilis, especially within high-risk populations, including people living with HIV.

The Great Imitator: The Many Faces of Syphilitic Skin Presentations.

We report the case of a 22-year-old heterosexual man presenting with a pruritic rash to the sexual health clinic. He was initially suspected of having a fungal rash by his general practitioner (GP) and treated with antifungals unsuccessfully. Subsequent testing revealed an active infection with Treponema pallidum. This was complicated by the concurrent fungal infection of the penile skin resulting in multiple lesions, requiring both antibiotic and antifungal treatment. With this case report, we hope to raise awareness amongst clinicians in non-traditional settings of the uncommon ways in which syphilis can present and to always consider it as a differential diagnosis, particularly in less likely populations.

Persistence of Treponema pallidum IgM antibodies in serum: What is their meaning?

We studied the detection of Treponema pallidum (TP)-IgM antibodies in the serum of 69 patients treated for syphilis. The persistence of TP-IgM antibodies in serum for more than 3 years was the only clue to suspect an active infection and, therefore, to investigate a central nervous system involvement.

Neurosyphilis with sequential respiratory complications: A case report highlighting diagnostic and treatment challenges.

In this case report, we describe the presentation and clinical course of a 25-year-old male with a complex medical history and a fatal outcome due to neurosyphilis. The diagnosis of neurosyphilis-related complications. Neurosyphilis, a variant of tertiary syphilis, is a rare condition but can present with a wide range of neurological symptoms. This makes its diagnosis challenging. The study aims to report and discuss neurosyphilis in a young male, resulting in respiratory complications, and explore the clinical presentation, diagnostic and process, treatment challenges it poses to a tertiary care setup of a third-world country regimen, and the profound significance of this particular case.

Serofast status in syphilis: Pathogenesis to therapeutics.

Syphilis, a sexually transmitted infection caused by Treponema pallidum, has been experiencing a rise in prevalence in recent years. "Syphilis serofast" describes a unique serological reaction in patients with syphilis whose clinical symptoms have resolved following consistent anti-syphilitic therapy, but the non-Treponema pallidum antigen serologic test is still positive. Syphilis serofast is a risk factor for syphilis recurrence, neurosyphilis, and multisystem involvement. Considering the current lack of comprehensive knowledge about the epidemiological characteristics, pathogenesis, and therapies of syphilis serofast, we conducted an online search of research relating to syphilis serofast over the last twenty years. Previous research has shown that the pathogenesis of syphilis serofast is mainly related to clinical factors, immune factors, syphilis subtypes, and T.pallidum membrane protein repeat gene antigen. There are two distinct viewpoints on the treatment of serofast: no excessive treatment and active treatment. In addition, serofast patients also showed two clinical outcomes: syphilis recurrence and persistent serofast status. This article systematically reviews the related factors, treatment, and clinical outcomes of syphilis serofast, provides a theoretical basis for its research, diagnosis, and treatment, and helps clinicians develop a follow-up treatment management plan for syphilis serofast.