Type I IFN dynamics orchestrate protective ICAM1+ neutrophil heterogeneity as an early checkpoint for survival in lethal viral infection.

The early host response influences outcomes following viral infection. Here, we leveraged variability in survival after intranasal vesicular stomatitis virus (VSV) challenge in genetically identical mice to retrospectively profile systemic immune responses associated with survival or lethality. Survival was strongly associated with a robust systemic type I interferon (IFN) surge within 24 h of infection, and blockade of type I IFN signaling during this narrow early window markedly reduced survival, establishing early IFN induction as a key determinant of outcome. This protective IFN surge rapidly remodeled the systemic immune landscape, inducing a specialized ICAM1+ neutrophil subset, primed within the bone marrow and characterized by a pro-inflammatory signature and enhanced phagocytic activity. Importantly, neutrophil-specific deletion of ICAM1 significantly reduced survival following viral infection. Together, these findings identify an early type I IFN-dependent checkpoint that shapes protective ICAM1+ neutrophil heterogeneity and disease trajectories, with implications for prognostic strategies and host-directed therapies.