Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming

Syphilis is a sexually transmitted disease caused by Treponema pallidum. The mechanisms enabling T. pallidum to persist despite macrophage eradication efforts in syphilis remain unclear. Pathogens can exploit senescent cells to enhance host susceptibility, and cellular senescence can be induced by pyroptosis, which known as inflammatory senescence. While recent studies have linked metabolic reprogramming to inflammatory senescence, their role in syphilis remained to be clarified. This study investigated the mechanisms of Tp47 on metabolic reprogramming and inflammatory senescence in macrophages. The results demonstrated that Tp47 triggered NLRP3 inflammasome-mediated pyroptosis by activating the phosphorylation of EIF2AK2 (a protein kinase), increasing senescence-associated pro-inflammatory cytokines secretion and leading to inflammatory senescence in macrophages. Additionally, Tp47 competitively bound to pyruvate kinase M2 (PKM2) with STUB1(a ubiquitin ligase), thereby inhibiting PKM2 ubiquitination degradation. By promoting the Y105 phosphorylation of PKM2, Tp47 modulated the intracellular function of PKM2, and facilitated PKM2-mediated metabolic reprogramming, which produced lactate that subsequently led to EIF2AK2 phosphorylation. Furthermore, inhibitors targeting EIF2AK2, lactate, glycolysis, and PKM2 effectively suppressed the inflammatory senescence induced by Tp47. In conclusion, Tp47 could mediate immune metabolic reprogramming through interaction with PKM2 to trigger macrophage inflammatory senescence. These discoveries offer a novel perspective for targeted therapies against syphilis.