The Regulatory Mechanisms of Treponema pallidum Enolase on Macrophages: From Enzymatic Activity to Signal Transduction

Syphilis, caused by the gram-negative bacterium Treponema pallidum, remains a significant global public health threat. Despite the efficacy of antibiotic treatment in controlling syphilis, the pathogenic mechanisms of T. pallidum, particularly its interactions with the host immune system, are not well understood. This study aimed to investigate the potential immunomodulatory role of T. pallidum enolase (Eno) in promoting macrophage apoptosis through the P2X7R and reactive oxygen species (ROS)/NF-κB pathways, offering new insights into the pathogen's immune evasion strategies. Bioinformatics analysis identified T. pallidum Eno as a hydrophilic cytoplasmic protein that plays a crucial role in glycolysis. In vitro experiments demonstrated that T. pallidum Eno can be successfully expressed and purified in Escherichia coli, resulting in significant induction of macrophage apoptosis. Mechanistic studies revealed that T. pallidum Eno activates caspase family members, decreases mitochondrial membrane potential, and triggers the apoptotic program in macrophages. Additionally, we found that T. pallidum Eno stimulates the production of ROS, subsequently activating the NF-κB signaling pathway and promoting the transcription of apoptosis-related genes. This study further highlights the role of T. pallidum Eno in modulating host immune responses by inducing the secretion of interleukin-8, interleukin-6, and interleukin-1β, which are involved in macrophage chemotaxis and activation. Collectively, these findings suggest that T. pallidum may exploit the host inflammatory response to enhance its dissemination and evade immune clearance. The multifaceted functions of T. pallidum Eno in cell metabolism and immune regulation provide new insights into the pathogenesis of syphilis and offer potential targets for therapeutic intervention.