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BackgroundThe syphilis epidemic continues to cause substantial morbidity and mortality worldwide, particularly in low- and middle-income countries, despite several recent disease control initiatives. Though our understanding of the pathogenesis of this disease and the biology of the syphilis agent, Treponema pallidum subsp. pallidum has improved over the last two decades, further research is necessary to improve clinical diagnosis and disease management protocols. Additionally, such research efforts could contribute to the identification of possible targets for the development of an effective vaccine to stem syphilis spread.MethodsThis study will recruit two cohorts of participants with active syphilis infection, one with de novo infection, one with repeat infection. Whole blood specimens will be collected from each study participant at baseline, 4, 12, 24, 36, and 48 weeks, to track specific markers of their immunological response, as well as to compare humoral reactivity to Treponema pallidum antigens between the two groups. Additionally, we will use serum specimens to look for unique cytokine patterns in participants with early syphilis. Oral and blood samples, as well as samples from any syphilitic lesions present, will also be collected to sequence any Treponema pallidum DNA found.DiscussionBy furthering our understanding of syphilis pathogenesis and human host immune response to Treponema pallidum, we will provide important data that will help in development of new point-of-care tests that could better identify active infection, leading to improved syphilis diagnosis and management. Findings could also contribute to vaccine development efforts.

This article was originally published under a CC BY-NC-SA License, but has now been made available under a CC BY 4.0 License.

The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss‐of‐function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red‐shifted green fluorescent protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy‐ and cell sorting–based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes. [ABSTRACT FROM AUTHOR]

Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur's rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens.

Background Histologic and serologic studies suggest the induction of local and systemic Treponema pallidum -specific CD4+ T-cell responses to T. pallidum infection. We hypothesized that T. pallidum -specific CD4+ T cells are detectable in blood and in the skin rash of secondary syphilis and persist in both compartments after treatment. Methods Peripheral blood mononuclear cells collected from 67 participants were screened by interferon-γ (IFN-γ) ELISPOT response to T. pallidum sonicate. T. pallidum -reactive T-cell lines from blood and skin were probed for responses to 89 recombinant T. pallidum antigens. Peptide epitopes and HLA class II restriction were defined for selected antigens. Results We detected CD4+ T-cell responses to T. pallidum sonicate ex vivo. Using T. pallidum -reactive T-cell lines we observed recognition of 14 discrete proteins, 13 of which localize to bacterial membranes or the periplasmic space. After therapy, T. pallidum -specific T cells persisted for at least 6 months in skin and 10 years in blood. Conclusions T. pallidum infection elicits an antigen-specific CD4+ T-cell response in blood and skin. T. pallidum -specific CD4+ T cells persist as memory in both compartments long after curative therapy. The T. pallidum antigenic targets we identified may be high-priority vaccine candidates. [ABSTRACT FROM AUTHOR]

Background Treponema pallidum prevalence and burden at oral and lesion sites in adults with early syphilis were assessed by quantitative polymerase chain reaction (qPCR). Factors associated with oral shedding were also examined. Methods Pretreatment oral and lesion swabs were collected from adults with early syphilis in a US multicenter syphilis treatment trial. Oral swabs were collected in the presence and absence of oral lesions. Following DNA extraction, qPCR and whole-genome sequencing (WGS) were performed to assess burden and strain variability. Results All 32 participants were male, mean age was 35 years, and 90.6% with human immunodeficiency virus (HIV). T. pallidum oral PCR positivity varied by stage: 16.7% primary, 44.4% secondary, and 62.5% in early latent syphilis. Median oral T. pallidum burden was highest in secondary syphilis at 63.2 copies/µL. Lesion PCR positivity was similar in primary (40.0%) and secondary syphilis (38.5%). Age 18–29 years was significantly associated with oral shedding (vs age 40+ years) in adjusted models. WGS identified 2 distinct strains. Conclusions T. pallidum DNA was directly detected at oral and lesion sites in a significant proportion of men with early syphilis. Younger age was associated with oral shedding. Ease of oral specimen collection and increased PCR availability suggest opportunities to improve syphilis diagnostic testing. Clinical Trials Registration. NCT03637660. [ABSTRACT FROM AUTHOR]

Background The incidence of syphilis continues to increase in the United States, yet little is known about Treponema pallidum genomic epidemiology within American metropolitan areas. Methods We performed whole-genome sequencing and tprK deep sequencing of 28 T. pallidum– containing specimens, collected mostly from remnant Aptima swab specimens from 24 individuals from Seattle Sexual Health Clinic during 2021–2022. Results All 12 individuals infected with Nichols-lineage strains were men who have sex with men, while a specific SS14 cluster (mean, 0.33 single-nucleotide variant) included 1 man who has sex with women and 5 women. All T. pallidum strains sequenced were azithromycin resistant via 23S ribosomal RNA A2058G mutation. Identical T. pallidum genomic sequences were found in pharyngeal and rectal swab specimens taken concurrently from the same individuals. The tprK sequences were less variable between patient-matched specimens and between epidemiologically linked clusters. We detected a 528–base pair deletion in the tprK donor site locus, eliminating 9 donor sites, in T. pallidum genomes of 3 individuals with secondary syphilis, associated with diminution of TprK diversity. Conclusions We developed an end-to-end workflow for public health genomic surveillance of T. pallidum from remnant Aptima swab specimens. tprK sequencing may assist in linking cases beyond routine T. pallidum genome sequencing. T. pallidum strains with deletions in tprK donor sites currently circulate and are associated with diminished TprK antigenic diversity. [ABSTRACT FROM AUTHOR]

A systematic review and meta-analysis conducted by Callado et al compared nonpenicillin antibiotics with benzathine penicillin G (BPG) for the treatment of syphilis. The meta-analysis included 5 studies that evaluated azithromycin as monotherapy for syphilis and concluded that ceftriaxone, azithromycin, and doxycycline are equivalent to BPG in terms of serologic cure rates for syphilis. However, the article points out that there is a high level of macrolide resistance in Treponema pallidum subsp pallidum (T pallidum), the bacteria that causes syphilis. As a result, azithromycin has not been recommended as a syphilis treatment option for nearly 20 years. The article advises caution against using azithromycin for syphilis treatment until genotypic resistance testing becomes widely available. The current recommendation is to use oral doxycycline as the primary alternative therapy for syphilis treatment. [Extracted from the article]