Syphilis, a re‐emerging public health problem worldwide caused by Treponema pallidum subsp pallidum (T. pallidum), usually induces systemic and chronic inflammation in hosts who do not receive timely therapy after exposing to high‐risk factors such as leprous sexual contact. Before the treatment, rapid and accurate detection of syphilis is essential. However, the existing detection methods, which focus on the treponemal or non‐treponemal antibody test, both have inherent limitations. For instance, both of them cannot distinguish the stage and severity of syphilis. Non‐treponemal test such as RPR, which is generally deemed to be used for assessing treatment response, is influenced by biological false positives. Therefore, it is imperative to seek out a new and effective diagnostic test. With recent advancements in molecular biology and whole‐genome sequencing, the molecular diagnosis has increased in popularity, especially the use of polymerase chain reaction (PCR). Here, we firstly present a mini‐review on the research of PCR detection methods used for syphilis diagnosis over the past decade, and we then compare these methodologies to assess their potential and the challenges faced. This information can provide a fresh perspective to help researchers address the current challenges.

Syphilis, a sexually transmitted disease (STD) caused by Treponema pallidum (T. pallidum), has had a worldwide resurgence in recent years and remains a public health threat. As such, there has been a great deal of research into clinical strategies for the disease, including diagnostic biomarkers and possible strategies for treatment and prevention. Although serological testing remains the predominant laboratory diagnostic method for syphilis, it is worth noting that investigations pertaining to the DNA of T. pallidum, non-coding RNAs (ncRNAs), chemokines, and metabolites in peripheral blood, cerebrospinal fluid, and other bodily fluids have the potential to offer novel perspectives on the diagnosis of syphilis. In addition, the global spread of antibiotic resistance, such as macrolides and tetracyclines, has posed significant challenges for the treatment of syphilis. Fortunately, there is still no evidence of penicillin resistance. Hence, penicillin is the recommended course of treatment for syphilis, whereas doxycycline, tetracycline, ceftriaxone, and amoxicillin are viable alternative options. In recent years, efforts to discover a vaccine for syphilis have been reignited with better knowledge of the repertoire of T. pallidum outer membrane proteins (OMPs), which are the most probable syphilis vaccine candidates. However, research on therapeutic interventions and vaccine development for human subjects is limited due to practical and ethical considerations. Thus, the preclinical model is ideal for conducting research, and it plays an important role in clinical transformation. Different preclinical models have recently emerged, such as in vitro culture and mouse models, which will lay a solid foundation for clinical treatment and prevention of syphilis. This review aims to provide a comprehensive summary of the most recent syphilis tactics, including detection, drug resistance treatments, vaccine development, and preclinical models in clinical practice.

Treponema pallidum is the pathogen that causes syphilis, a sexually transmitted disease; however, the pathogenic mechanism of this organism remains unclear. Tp92 is the only T. pallidum outer membrane protein that has structural features similar to the outer membrane proteins of other Gram‐negative bacteria, but the exact functions of this protein remain unknown. In the present study, we demonstrated that the recombinant Tp92 protein can induce human mononuclear cell death. Tp92 mediated the human monocytic cell line derived from an acute monicytic leukemia patient (THP‐1) cell death by recognizing CD14 and/or TLR2 on cell surfaces. After the stimulation of THP‐1 cells by the Tp92 protein, Tp92 may induce atypical pyroptosis of THP‐1 cells via the pro‐caspase‐1 pathway. Meanwhile, this protein caused the apoptosis of THP‐1 cells via the receptor‐interacting protein kinase 1/caspase‐8/aspase‐3 pathway. Tp92 reduced the number of monocytes among peripheral blood mononuclear cells. Interestingly, further research showed that Tp92 failed to increase the tumour necrosis factor‐α, interleukin (IL)‐1β, IL‐6, IL‐10, IL‐18 and monocyte chemotactic protein 1 (MCP)‐1 levels but slightly elevated the IL‐8 levels via the Nuclear Factor (NF)‐κB pathway in THP‐1 cells. The data suggest that Tp92 recognizes CD14 and TLR2, transfers the signal to a downstream pathway, and activates NF‐κB to mediate the production of IL‐8. This mechanism may help T. pallidum escape recognition and elimination by the host innate immune system.