Microbial PAMPs-PRR driven neuroimmune signaling in the development of post-infectious persistent pain

Post-infectious persistent pain (PIPP) is a common long-term outcome of infection, but the link between transient infection and persistent pain remains unclear. Traditional explanations, such as tissue injury, residual inflammation, and nerve damage, do not fully explain pain persistence after pathogen clearance. This review proposes that signaling between pathogen-associated molecular patterns and pattern recognition receptors (PAMP–PRR) is a key mechanistic bridge from acute infection to persistent pain. Microbial ligands from bacterial, viral, fungal, and parasitic pathogens activate PRRs in immune cells, sensory neurons, glia, and epithelial cells, triggering shared neuroimmune programs that include inflammatory amplification, neuron–immune crosstalk, glial activation, and sensitization of peripheral and central pain pathways. Persistent microbial products, viral latency, repeated antigen exposure, and trained immunity may maintain these circuits and promote a shift from PAMP-driven responses to damage-associated molecular pattern (DAMP)-mediated sterile neuroinflammation. These observations reframe PIPP as a dynamic neuroimmune disorder and support biomarker-informed, stage-specific therapies aimed at restoring neuroimmune homeostasis while preserving host defense.