Treponema pallidum cytolytic toxin, Tp0649, induces apoptosis in THP-1 macrophages via the ERK MAPK, p38 MAPK, PI3K/AKT, and NF-κB signaling pathways.

Syphilis is a persistent sexually transmitted disease caused by Treponema pallidum subsp. Pallidum (T. pallidum), a dense spirochete. Severe multi-organ failure is often observed in late-stage infections. T. pallidum exhibits cytotoxic activity in vitro and acts pathogenic through the production of toxic substances. Cytolysin (tly), which damages the target cells, plays a key role in the pathogenicity of lysogenic cytotoxins. Cell damage is mainly caused by three toxins: pore-forming toxins, phospholipases (lipasic toxins), and surface-active toxins. Genomic sequencing has revealed that tlyC (Tp0649) encodes a potential lysogenic cytotoxin in T. pallidum; however, its specific functions remain unknown. In this study, we found that the recombinant Tp0649 protein activated procaspase-8 via the extracellular signal-regulated kinase mitogen-activated protein kinase (MAPK), p38 MAPK, phosphoinositide 3-kinase/protein kinase B, and nuclear factor-κB signaling pathways. Alternatively, this protein caused damage to the mitochondria, leading to reactive oxygen species overload, which activated procaspase-3 and induced apoptosis in human monocytes. These findings provide valuable perspectives to understand the potential molecular mechanisms and suggest potential therapeutic targets for the treatment of syphilis.