Interferon regulatory factor 5 associated neutrophil reprogramming by trained immunity protects against lethal-dose bacterial sepsis

neutrophil state; upon lethal re-challenge, these cells differentiate into Cd274⁺ checkpoint-enriched and Fth1⁺ ROS-adaptive subsets. Functionally, primed-then-challenged mice exhibit amplified early cytokine responses, increased reactive oxygen species and neutrophil extracellular trap formation, and reduced bacterial burden with improved survival compared with lethal controls. Consistent with a cross-species program, Irf5 overexpression in zebrafish similarly enhances resistance to patient-derived pathogens. Mechanistically, Irf5-MyD88 signaling links priming to neutrophil fate diversification and heightened antibacterial function. These findings suggest Irf5-based modulation may inform future strategies to strengthen innate immunity and improve host resistance in infectious disease settings.