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

Intra-abdominal infection is a major driver of sepsis with limited therapeutic options. Although innate immune memory (trained immunity) has been studied in monocytes and macrophages, its role in neutrophils is unclear. Here, using mouse and zebrafish models of bacterial peritonitis, we show that a low-dose bacterial exposure induces an interferon regulatory factor 5 (Irf5) + 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.