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Nature Reviews. Microbiology Dec 2016The past two decades have seen a worldwide resurgence in infections caused by Treponema pallidum subsp. pallidum, the syphilis spirochete. The well-recognized capacity... (Review)
Review
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.
Topics: Bacterial Outer Membrane Proteins; Bacterial Proteins; Genomics; Humans; Immune Evasion; Sequence Alignment; Syphilis; Toll-Like Receptor 2; Treponema pallidum
PubMed: 27721440
DOI: 10.1038/nrmicro.2016.141 -
Clinical Microbiology Reviews Jan 2006Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subsp. pallidum. Clinical manifestations separate the disease into stages; late stages of... (Review)
Review
Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subsp. pallidum. Clinical manifestations separate the disease into stages; late stages of disease are now uncommon compared to the preantibiotic era. T. pallidum has an unusually small genome and lacks genes that encode many metabolic functions and classical virulence factors. The organism is extremely sensitive to environmental conditions and has not been continuously cultivated in vitro. Nonetheless, T. pallidum is highly infectious and survives for decades in the untreated host. Early syphilis lesions result from the host's immune response to the treponemes. Bacterial clearance and resolution of early lesions results from a delayed hypersensitivity response, although some organisms escape to cause persistent infection. One factor contributing to T. pallidum's chronicity is the paucity of integral outer membrane proteins, rendering intact organisms virtually invisible to the immune system. Antigenic variation of TprK, a putative surface-exposed protein, is likely to contribute to immune evasion. T. pallidum remains exquisitely sensitive to penicillin, but macrolide resistance has recently been identified in a number of geographic regions. The development of a syphilis vaccine, thus far elusive, would have a significant positive impact on global health.
Topics: Amino Acid Sequence; Bacterial Outer Membrane Proteins; Humans; Molecular Sequence Data; Sequence Alignment; Syphilis; Treponema pallidum
PubMed: 16418521
DOI: 10.1128/CMR.19.1.29-49.2006 -
BMJ (Clinical Research Ed.) Jun 2019
Topics: Agglutination Tests; Anti-Bacterial Agents; Chancre; Disease Transmission, Infectious; Female; Humans; Incidence; Luminescent Measurements; Male; Sexually Transmitted Diseases, Bacterial; Syphilis; Syphilis Serodiagnosis; Treponema pallidum
PubMed: 31253629
DOI: 10.1136/bmj.l4159 -
Current Topics in Microbiology and... 2018The outer membrane (OM) of Treponema pallidum, the uncultivatable agent of venereal syphilis, has long been the subject of misconceptions and controversy. Decades ago,... (Review)
Review
The outer membrane (OM) of Treponema pallidum, the uncultivatable agent of venereal syphilis, has long been the subject of misconceptions and controversy. Decades ago, researchers postulated that T. pallidum's poor surface antigenicity is the basis for its ability to cause persistent infection, but they mistakenly attributed this enigmatic property to the presence of a protective outer coat of serum proteins and mucopolysaccharides. Subsequent studies revealed that the OM is the barrier to antibody binding, that it contains a paucity of integral membrane proteins, and that the preponderance of the spirochete's immunogenic lipoproteins is periplasmic. Since the advent of recombinant DNA technology, the fragility of the OM, its low protein content, and the lack of sequence relatedness between T. pallidum and Gram-negative outer membrane proteins (OMPs) have complicated efforts to characterize molecules residing at the host-pathogen interface. We have overcome these hurdles using the genomic sequence in concert with computational tools to identify proteins predicted to form β-barrels, the hallmark conformation of OMPs in double-membrane organisms and evolutionarily related eukaryotic organelles. We also have employed diverse methodologies to confirm that some candidate OMPs do, in fact, form amphiphilic β-barrels and are surface-exposed in T. pallidum. These studies have led to a structural homology model for BamA and established the bipartite topology of the T. pallidum repeat (Tpr) family of proteins. Recent bioinformatics has identified several structural orthologs for well-characterized Gram-negative OMPs, suggesting that the T. pallidum OMP repertoire is more Gram-negative-like than previously supposed. Lipoprotein adhesins and proteases on the spirochete surface also may contribute to disease pathogenesis and protective immunity.
Topics: Bacterial Outer Membrane Proteins; Humans; Periplasm; Syphilis; Treponema pallidum
PubMed: 28849315
DOI: 10.1007/82_2017_44 -
Current Protocols Aug 2022Although the isolation of Treponema pallidum subsp. pallidum (T. pallidum) from a syphilis patient dates to 1912, for the duration of the 20 century, this pathogen has...
Although the isolation of Treponema pallidum subsp. pallidum (T. pallidum) from a syphilis patient dates to 1912, for the duration of the 20 century, this pathogen has remained an exceedingly difficult organism to study due to the lack of a system to support its viability in vitro. This limitation, in turn, has precluded the application of genetic engineering techniques via transformation and subsequent selection of T. pallidum transformants. A recently described method for in vitro cultivation of T. pallidum, however, has made it possible for us to experiment with transformation and selection methods. Here we describe the approach that we adopted to successfully transform T. pallidum with foreign DNA and select the resulting recombinant strain using kanamycin. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Transformation of T. pallidum Support Protocol 1: Quantification of T. pallidum in suspensions using dark-field microscopy Support Protocol 2: Counting cells using a hemacytometer Basic Protocol 2: Selection, initial passaging, and expansion of transformed cultures Basic Protocol 3: Isolation of a clonal strain through limiting dilution.
Topics: Humans; Syphilis; Treponema; Treponema pallidum
PubMed: 35976045
DOI: 10.1002/cpz1.507 -
Treponema pallidum Macrolide Resistance and Molecular Epidemiology in Southern Africa, 2008 to 2018.Journal of Clinical Microbiology Sep 2021Treponema pallidum macrolide resistance and clinical treatment failure have emerged rapidly within communities where macrolides have been used as convenient, oral...
Treponema pallidum macrolide resistance and clinical treatment failure have emerged rapidly within communities where macrolides have been used as convenient, oral therapeutic alternatives to benzathine penicillin G for syphilis or for other clinical indications. Macrolides are not included in the South African syndromic management guidelines for genital ulcer disease; however, in 2015, a 1-g dose of azithromycin was incorporated into treatment algorithms for genital discharge. We determined the prevalence of 23S rRNA macrolide resistance-associated point mutations in 135 T. pallidum-positive surveillance specimens from Botswana, Zimbabwe, and South Africa between 2008 and 2018. Additionally, we investigated the association between macrolide resistance, T. pallidum strain type, and HIV coinfection. A significant increase in the prevalence of the A2058G macrolide resistance-associated point mutation was observed in specimens collected after 2015. There was a high level of molecular heterogeneity among T. pallidum strains circulating in the study communities, with strain type 14d/f being the most predominant in South Africa. Fourteen novel strain types, derived from three new gene restriction fragment length polymorphism patterns and seven new gene sequence types, were identified. There was an association between A2058G-associated macrolide resistance and T. pallidum strain types 14d/f and 14d/g but no association between T. pallidum macrolide resistance and HIV coinfection. The majority of T. pallidum strains, as well as strains containing the A2058G mutation, belonged to the SS14-like clade. This is the first study to extensively detail the molecular epidemiology and emergence of macrolide resistance in T. pallidum in southern Africa.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Macrolides; Molecular Epidemiology; Treponema pallidum
PubMed: 34346717
DOI: 10.1128/JCM.02385-20 -
PLoS Neglected Tropical Diseases Dec 2021In spite of its immutable susceptibility to penicillin, Treponema pallidum (T. pallidum) subsp. pallidum continues to cause millions of cases of syphilis each year...
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.
Topics: Bacterial Proteins; Bacterial Vaccines; Base Sequence; Female; Genetic Variation; Genome, Bacterial; Humans; Madagascar; Male; Phylogeny; Polymorphism, Single Nucleotide; Syphilis; Treponema pallidum
PubMed: 34936652
DOI: 10.1371/journal.pntd.0010063 -
Molecular Immunology Jul 2022Treponema pallidum is a "stealth pathogen" responsible for infectious sexually transmitted diseases. Although neutrophils are usually present in skin lesions of early...
Treponema pallidum is a "stealth pathogen" responsible for infectious sexually transmitted diseases. Although neutrophils are usually present in skin lesions of early syphilis, the role of these cells in T. pallidum infection has barely been investigated. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis usually accelerates this process. Here, we demonstrated that human polymorphonuclear neutrophils (hPMNs) could phagocytose T. pallidum in vitro. An unexpected discovery was that T. pallidum inhibited hPMNs apoptosis markedly in an opsonin-independent manner. Furthermore, this phenomenon was not affected by bacterial viability, as detected by annexin V, morphology studies, and TUNEL staining. Exploration of the underlying mechanism showed that expression of the cleaved forms of caspase-3, -8, and -9 and effector caspase activity were diminished significantly in T. pallidum-infected hPMNs. T. pallidum also impaired staurosporine- and anti-Fas-induced signaling for neutrophil apoptosis. Of note, these effects were accompanied by inducing the autocrine production of the anti-apoptotic cytokine IL-8. Taken together, our data revealed that T. pallidum could inhibit the apoptosis of hPMNs through intrinsic and extrinsic pathways and provide new insights for understanding the pathogenicity mechanisms of T. pallidum.
Topics: Apoptosis; Humans; Neutrophils; Opsonin Proteins; Phagocytosis; Treponema pallidum
PubMed: 35597181
DOI: 10.1016/j.molimm.2022.04.012 -
Transactions of the Royal Society of... Jul 2021Female sex workers (FSWs) are an especially vulnerable group for syphilis and other sexually transmitted infection (STIs). This study determined the prevalence of...
BACKGROUND
Female sex workers (FSWs) are an especially vulnerable group for syphilis and other sexually transmitted infection (STIs). This study determined the prevalence of syphilis in FSWs and factors associated with this disease in the Marajó Archipelago (northern Brazil), as well as the frequency of point mutations (A2058G and A2059G) in the 23S rRNA gene of Treponema pallidum and coinfections with hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV).
METHODS
FSWs were diagnosed using a rapid qualitative test and the isolates were evaluated for the presence of point mutations by real-time PCR. Blood samples with T. pallidum were tested for the presence of HBV, HCV and HDV by ELISA and confirmed by real-time PCR. The factors associated with syphilis were identified using Poisson regression models.
RESULTS
Overall, 41.1% FSWs tested positive for syphilis and 23.5% were infected with strains having A2058G/A2059G point mutations. HBV (23.0%) and HCV (8.1%) were detected among FSWs with syphilis. Six factors were associated with syphilis: low levels of education, reduced income, drug use, unprotected sex, a lengthy career in prostitution and a lack of regular medical check-ups.
CONCLUSIONS
These findings indicate an urgent need for implementation of effective strategies to diagnose, prevent and treat syphilis, as well as other STIs, in this Brazilian region.
Topics: Brazil; Coinfection; Drug Resistance, Bacterial; Female; Humans; Mutation; Prevalence; Risk Factors; Sex Workers; Syphilis; Treponema pallidum
PubMed: 33210137
DOI: 10.1093/trstmh/traa127 -
PLoS Neglected Tropical Diseases Nov 2011Syphilis is resurgent in many regions of the world. Molecular typing is a robust tool for investigating strain diversity and epidemiology. This study aimed to review... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Syphilis is resurgent in many regions of the world. Molecular typing is a robust tool for investigating strain diversity and epidemiology. This study aimed to review original research on molecular typing of Treponema pallidum (T. pallidum) with three objectives: (1) to determine specimen types most suitable for molecular typing; (2) to determine T. pallidum subtype distribution across geographic areas; and (3) to summarize available information on subtypes associated with neurosyphilis and macrolide resistance.
METHODOLOGY/PRINCIPAL FINDINGS
Two researchers independently searched five databases from 1998 through 2010, assessed for eligibility and study quality, and extracted data. Search terms included "Treponema pallidum," or "syphilis," combined with the subject headings "molecular," "subtyping," "typing," "genotype," and "epidemiology." Sixteen eligible studies were included. Publication bias was not statistically significant by the Begg rank correlation test. Medians, inter-quartile ranges, and 95% confidence intervals were determined for DNA extraction and full typing efficiency. A random-effects model was used to perform subgroup analyses to reduce obvious between-study heterogeneity. Primary and secondary lesions and ear lobe blood specimens had an average higher yield of T. pallidum DNA (83.0% vs. 28.2%, χ(2) = 247.6, p<0.001) and an average higher efficiency of full molecular typing (80.9% vs. 43.1%, χ(2) = 102.3, p<0.001) compared to plasma, whole blood, and cerebrospinal fluid. A pooled analysis of subtype distribution based on country location showed that 14d was the most common subtype, and subtype distribution varied across geographic areas. Subtype data associated with macrolide resistance and neurosyphilis were limited.
CONCLUSIONS/SIGNIFICANCE
Primary lesion was a better specimen for obtaining T. pallidum DNA than blood. There was wide geographic variation in T. pallidum subtypes. More research is needed on the relationship between clinical presentation and subtype, and further validation of ear lobe blood for obtaining T. pallidum DNA would be useful for future molecular studies of syphilis.
Topics: Genotype; Humans; Molecular Epidemiology; Molecular Typing; Phylogeography; Syphilis; Treponema pallidum
PubMed: 22087340
DOI: 10.1371/journal.pntd.0001273