Performance of novel infection phase-dependent antigens in syphilis serodiagnosis and treatment efficacy determination

Li, Wen; Deng, Meixia; Zhang, Xiao­hong; Yin, Wen; Zhao, Tiantian; Zeng, Tiebing; Liu, Shuangquan; Xiao, Yao; Zhang, Li; Luo, Xi; Zhao, Feijun

doi:10.1016/j.cca.2018.10.017

Cited by 13 publications

(17 citation statements)

References 21 publications

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“…In addition, ELISA presents usually higher diagnostic performance compared to nontreponemal assays [11]. However, its performance depends on the antigens employed to detect the anti-T. pallidum antibodies presence and on the clinical stage of the infection [12].…”

Section: Introductionmentioning

confidence: 99%

Performance of Treponema pallidum recombinant proteins in the serological diagnosis of syphilis

et al. 2020

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Syphilis serodiagnosis is challenging because distinct clinical forms of the infection may influence serological performance and discordant results between tests make clinical decisions difficult. Several recombinant Treponema pallidum-proteins have already been tested for syphilis diagnosis and they are critical to achieve high accuracy in serological testing. Our aim was to assess the varied from performance of T. pallidum-recombinant proteins TmpA, TpN17 and TpN47 for syphilis serodiagnosis. The proteins were evaluated using sera of 338 T. pallidum-negative, 173 T. pallidum-positive individuals and 209 sera from individuals infected with unrelated diseases. The diagnostic potential was validated by analysis of ROC curves. In the liquid microarray analyses, the ROC curve varied from 99.0% for TmpA and TpN17 to 100% for TpN47. The sensitivity score yielded values of up to 90% for TpN17, 100% for TpN47 and 80.0% for TmpA. The lowest and highest specificity values were presented by TpN47 (91.9%) and TmpA antigens (100%), respectively. TpN47 showed the highest accuracy score (95.5%) among all the recombinant proteins assayed. For the ELISA, the ROC curve was 97.2%, 91.8% and 81.6% for TpN17, TmpA and TpN47, respectively. TpN17 and TmpA yielded a sensitivity of 69.9%, while TpN47 obtained a value of 53.8%. Specificity was almost 100% for all three proteins. No cross-reaction was observed for TpN17 in the serum samples from non-bacterial infections. Regarding leptospirosis-positive samples, cross-reactivity score was varied from 8.6 to 34.6%. This is most probably due to conservation of the epitopes in these proteins across bacteria. The use of recombinant proteins in immunoassays for syphilis diagnosis was showed provide greater reliability to results of the treponemal assays. Despite the low sensitivity, the proteins showed high diagnostic capacity due to the AUC values found. However, an improvement in sensitivity could be achieved when antigenic mixtures are evaluated.

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Section: Introductionmentioning

confidence: 99%

Performance of Treponema pallidum recombinant proteins in the serological diagnosis of syphilis

et al. 2020

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“…pallidum . It is primarily transmitted either through sexual contact or by vertical, transplacental migration, resulting in congenital syphilis [9, 44, 45]. Due to the known limitation of working with this pathogen, investigators have heavily relied on comparative genomics to identify putative-surface-exposed virulence factors of this pathogen.…”

Section: Discussionmentioning

confidence: 99%

“…Another limitation of studying T . pallidum is that its envelope is exceedingly fragile compared to more conventional Gram-negative organisms [9] due to the absence of lipopolysaccharide (LPS) in its outer membrane and a very thin peptidoglycan layer that is only loosely associated to the outer membrane. Furthermore, T .…”

Section: Introductionmentioning

confidence: 99%

Analysis of host cell binding specificity mediated by the Tp0136 adhesin of the syphilis agent Treponema pallidum subsp. pallidum

2019

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Background Syphilis affects approximately 11 million people each year globally, and is the third most prevalent sexually transmitted bacterial infection in the United States. Inability to independently culture and genetically manipulate Treponema pallidum subsp. pallidum , the causative agent of this disease, has hindered our understanding of the molecular mechanisms of syphilis pathogenesis. Here, we used the non-infectious and poorly adherent B314 strain of the Lyme disease-causing spirochete, Borrelia burgdorferi , to express two variants of a known fibronectin-binding adhesin, Tp0136, from T . pallidum SS14 and Nichols strains. Using this surrogate system, we investigated the ability of Tp0136 in facilitating differential binding to mammalian cell lines offering insight into the possible role of this virulence factor in colonization of specific tissues by T . pallidum during infection. Principal findings Expression of Tp0136 could be detected on the surface of B . burgdorferi by indirect immunofluorescence assay using sera from a secondary syphilis patient that does not react with intact B314 spirochetes transformed with the empty vector. Increase in Tp0136-mediated adherence of B314 strain to human epithelial HEK293 cells was observed with comparable levels of binding exhibited by both Tp0136 alleles. Adherence of Tp0136-expressing B314 was highest to epithelial HEK293 and C6 glioma cells. Gain in binding of B314 strain expressing Tp0136 to purified fibronectin and poor binding of these spirochetes to the fibronectin-deficient cell line (HEp-2) indicated that Tp0136 interaction with this host receptor plays an important role in spirochetal attachment to mammalian cells. Furthermore, preincubation of these cell lines with fibronectin-binding peptide from Staphylococcus aureus FnbA-2 protein significantly inhibited binding of B314 expressing Tp0136. Conclusions Our results show that Tp0136 facilitates differential level of binding to cell lines representing various host tissues, which highlights the importance of this protein in colonization of human organs by T . pallidum and resulting syphilis pathogenesis.

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“…Understanding lipoprotein-induced immune regulation will help elucidate the pathogenesis of innate immunity and subsequent adaptation mechanisms, which may be related to inflammation and related vaccine development in spirochetes disease. Studies have shown that lipoprotein Tp0768 is an infection-dependent antigen that has a high value for the clinical diagnosis of syphilis serology (Liu et al 2019;Runina et al 2018). However, little is known about the role of Tp0768 in inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Tp0768 is considered to be a T. pallidum infectiondependent antigen (Gerber et al 1996). Previous studies have shown that high immunogenic Tp0768 (also known as TpN44.5 or TmpA) showed high sensitivity and specificity for the serological diagnosis of syphilis (Liu et al 2019;Backhouse and Nesteroff 2001). However, the pathogenesis of Tp0768 is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Treponema pallidum protein Tp0768 promotes proinflammatory cytokine secretion of macrophages through ER stress and ROS/NF-κB pathway

Zhou

Cai

et al. 2020

Appl Microbiol Biotechnol

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In response to danger signals, macrophages rapidly produce many inflammatory cytokines that trigger the cascade release of inflammatory mediators, leading to tissue damage, which is an important cause of clinical manifestations of syphilis at all stages. However, we still know very little about the specific mechanism of this process. Tp0768 is an infection-stage-dependent antigen that plays an important role in the infection of Treponema pallidum. In this study, we demonstrated that Tp0768 stimulation of macrophages can cause IL-1β, IL-6, and IL-8 mRNA expression levels to increase in a dose-and time-dependent manner. Further research showed that Tp0768 activated ER stress and the ROS/NF-κB pathway in macrophages. Inhibition of ER stress and the ROS/NF-κB pathway inhibited the expression of IL-1β, IL-6, and IL-8 induced by Tp0768. In addition, pretreatment with a PERK pathway inhibitor significantly reduced the expression of the NF-κB and JNK pathways, while also downregulating the expression of IL-1β, IL-6, and IL-8. Tp0768 stimulation can activate IRE1α/XBP-1 signaling and participate in the induction of inflammatory cytokines through the JNK pathway. These findings indicate that Tp0768 promotes the secretion of proinflammatory cytokines IL-1β, IL-6, and IL-8 by macrophages through ER stress and the ROS/NF-κB pathway, which are also involved in the activation of the NF-κB and JNK pathways that are induced by the PERK pathway and activation of IRE1α/XBP-1 signaling. Key points • This study found for the first time that the recombinant Treponema pallidum protein Tp0768 promotes the production of IL-1β, IL-6, and IL-8 by macrophages through ER stress. • Recombinant Treponema pallidum protein Tp0768 regulates the ROS/NF-κB pathway through ER stress. • ER stress-related pathway PERK induces the expression of IL-1β, IL-6, and IL-8 by activating the NF-κB pathway and the JNK pathway. • IRE1α can induce the splicing of XBP-1mRNA and activate the JNK pathway.

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Performance of novel infection phase-dependent antigens in syphilis serodiagnosis and treatment efficacy determination

Cited by 13 publications

References 21 publications

Performance of Treponema pallidum recombinant proteins in the serological diagnosis of syphilis

Performance of Treponema pallidum recombinant proteins in the serological diagnosis of syphilis

Analysis of host cell binding specificity mediated by the Tp0136 adhesin of the syphilis agent Treponema pallidum subsp. pallidum

Recombinant Treponema pallidum protein Tp0768 promotes proinflammatory cytokine secretion of macrophages through ER stress and ROS/NF-κB pathway

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