Background Although angiogenesis is an obvious pathological manifestation in the pathogenesis of syphilis, little is known about the underlying mechanisms of angiogenesis induced by reactions to Treponema pallidum antigens.Objective In this study, we sought to determine the role of recombinant T. pallidum Tp47 in promoting angiogenesis in endothelial cells and the related mechanism.Methods Evaluation of the pro-angiogenic activity of recombinant T. pallidum Tp47 in human umbilical vein endothelial cells (HUVECs) was assessed, and the balance of matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) and the mechanisms underlying the involvement of Akt/mTOR/S6 pathways in this process were explored.Results Under stimulation by Tp47, HUVECs exhibited obvious proliferation, migration and tube formation. In addition, the apparent promotion of angiogenesis by Tp47 was observed using a zebrafish embryo model. During angiogenesis, the levels of MMP-1 and MMP-10 were significantly elevated, whereas those of TIMP-1 and TIMP-2 did not change. In addition, after transfection with siRNAMMP-1 and siRNAMMP-10, migration and tube formation were significantly inhibited. Akt/mTOR/S6 signalling was found to be involved in upregulating MMP-1 and MMP-10 expression, and the sequential blockade of steps in the pathways effectively prevented Tp47-induced angiogenesis. ConclusionThe results reveal the underlying mechanism of angiogenesis promoted by Tp47, namely, upregulating MMP-1 and MMP-10 expression to disrupt the MMP/TIMP balance through the Akt/mTOR/S6 pathway. These findings contribute to our understanding of the pathophysiology of syphilis. At the second stage (secondary syphilis), T. pallidum causes a plethora of clinical manifestations characterized by vascular inflammation and increased angiogenesis. 5,6 In tertiary syphilis, unresolved angiogenesis is the underlying mechanism responsible for skeletal changes. 7 Overall, angiogenesis appears to play a pivotal role in syphilis pathogenesis, as with other diseases (e.g. cancer, infections and immune disorders). 8 † These authors contributed equally to this work.

Background Elucidating the mechanism of the macrophage phagocytic response will improve our knowledge of host defence against Treponema pallidum. Objective To explore whether autophagy promotes T. pallidum phagocytosis and clearance via the NLRP3 inflammasome in macrophages. Methods The interactions between autophagy and phagocytosis and the role of NLRP3 in these processes in T. pallidum‐treated macrophages were investigated through experiments using human monocytic cell line (THP‐1)‐derived macrophages. Treponema pallidum clearance after phagocytosis was evaluated by inoculating rabbits with macrophage–treponeme mixtures. Results Activation of autophagy and phagocytosis in T. pallidum‐treated macrophages occurred in a dose‐ and time‐dependent manner. The percentage of spirochete‐positive macrophages (22.34% vs. 70.93%, P < 0.001) and spirochete internalization (MFI: 9.62 vs. 20.33, P < 0.001) were notably reduced by silencing Beclin1. Inoculation of macrophage–treponeme mixtures into rabbits showed a 3.00‐day delay in lesion development (17.55 ± 3.73 vs. 14.55 ± 1.99 days) and decreased lesion numbers [11 (36.7%) vs. 20 (66.7%) of 30; χ2 = 5.406, P = 0.020] in the control compared with the si‐Beclin1 group. Furthermore, silencing NLRP3 decreased the mRNA and protein levels of Beclin‐1 and LC3B [mRNA: 49.86% and 43.02%; protein: 22.31% and 24.24%, respectively, differing significantly from the control group (P < 0.001)] and reduced the percentage of spirochete‐positive macrophages (30.29% vs. 70.53%, P < 0.001) and spirochete internalization (MFI: 9.82 vs. 19.33, P < 0.001). Conclusion Treponema pallidum induces autophagy in macrophages to promote phagocytosis and clearance. The NLRP3 inflammasome modulates autophagy and phagocytosis in vitro. These data may be useful for understanding the host–pathogen relationship and establish the groundwork for strategies to combat syphilis.

Background Global metabolomics analysis can provide substantial information on energy metabolism, physiology, possible diagnostic biomarkers and intervention strategies for pathogens. Objective To gain a better understanding of the mechanisms of syphilis and analysis of serum metabolite profiles in syphilis patients. Methods We conducted an untargeted metabolomics analysis of serum from 20 syphilis patients and 20 healthy controls. Results A total of 2890 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Distinct differential metabolites were identified by principal component analysis, partial least squares‐discriminant analysis and hierarchical clustering analysis. Furthermore, five metabolites were identified as significantly different by Student's t‐test, including trimethylamine N‐oxide, l‐arginine, lysoPC(18:0), betaine and acetylcarnitine. KEGG analysis showed that these differential metabolites were in various pathways, including Chagas disease, fatty acid biosynthesis, primary bile acid biosynthesis, Salmonella infection, ABC transporters, glycerophospholipid metabolism and choline metabolism. Among them, trimethylamine N‐oxide was 3.922 times in patients with syphilis than healthy controls. Conclusion Trimethylamine N‐oxide may be used as an indicator to distinguish between syphilis patients and healthy controls. The changes in these metabolites suggest that Treponema pallidum affects the normal metabolic activity of host cells, providing some clues for elucidating the pathogenesis of T. pallidum.