Neutrophil Biology and Fate Reprogramming in Bacterial Infections: Mechanisms, Plasticity, and Therapeutic Targeting

Neutrophils are essential leukocytes in bacterial infections, with their fate and immune regulation critically shaping disease outcomes. They eliminate pathogens through phagocytosis, degranulation, oxidative burst-mediated killing, and the release of neutrophil extracellular traps (NETs), yet these defenses can also trigger excessive inflammation and tissue damage. Recent advances, including single-cell and spatial transcriptomic profiling, have revealed remarkable neutrophil plasticity and subset heterogeneity, challenging the long-standing view of these cells as short-lived, uniform effectors. This review outlines an integrated framework of neutrophil immunity in bacterial infections, beginning with their development, recruitment, and in situ antimicrobial defense programs. We then examine how neutrophils adapt through immune signaling pathways, effector mechanisms, and fate-determining death programs that actively reshape inflammation and resolution. Within these adaptations, we highlight how host-derived cytokines, lipid mediators, and metabolic cues reprogram neutrophil functions toward either protective antimicrobial roles or pathological tissue-damaging programs. In parallel, bacterial pathogens exploit these same pathways to evade immune clearance. We further detail emerging therapeutic strategies targeting immune checkpoints, signaling nodes, and fate-regulating programs, offering promising avenues to recalibrate neutrophil activity, enhance bacterial control, and reduce immunopathology. To exemplify these principles in vivo, we focus on two granulomatous diseases, tuberculosis and paratuberculosis, where neutrophils exhibit context-dependent dysfunctions, including excessive NETosis, metabolic rewiring, and impaired phagocytic clearance. Collectively, these insights position neutrophil fate reprogramming as a central regulatory axis of leukocyte immunity and a tractable target for host-directed therapy in bacterial infections.