Training the Lung, Taming the NETs

Respiratory infections remain a major global health threat, and recent epidemics have shown that treating the pathogen alone is not enough. In severe influenza, COVID-19, RSV, and bacterial pneumonia, lung failure often results less from microbial load and more from the host’s overactive immune response. Two key processes, neutrophil extracellular traps (NETs) and trained immunity, sit at the center of this shift toward host-focused intervention. Although both are innate defenses, they are usually discussed in isolation: NETs in the context of acute inflammation and thrombosis, and trained immunity in the context of vaccines, epigenetic reprogramming, and metabolic adaptation. Yet in the lung, these mechanisms function as interconnected elements of early defense. This editorial argues that effective therapies should no longer treat them as separate phenomena but instead co-target NET regulation and trained-immunity pathways as a unified, host-directed strategy to reduce immunopathology and improve outcomes in severe respiratory infections.