Neutrophil Heterogeneity in Infectious Disease: Developmental Origins, Functional States, and Insights from Herpes Simplex Virus Type 1 Keratitis

Neutrophils were long regarded as a uniform population of short-lived phagocytes that execute a stereotyped antimicrobial program before dying at the site of infection. Single-cell transcriptomics, mass cytometry, and spatial imaging have replaced this view with a picture of neutrophils as a developmental continuum, beginning with committed bone marrow precursors and extending through circulating, aged, suppressive, and tissue-imprinted states, each carrying a distinct transcriptional and functional signature. This review traces how granulopoiesis generates that continuum, how chemokine axes such as CXCR4-CXCL12 and CXCR2 govern bone marrow release and peripheral trafficking, and how infection reshapes the balance between protective and pathogenic neutrophil programs, including neutrophil extracellular trap formation, immunometabolic reprogramming, and tissue-specific adaptation in lung, gut, liver, and central nervous system compartments. Particular attention is given to the eye, where neutrophils confer early antiviral protection against herpes simplex virus type 1 keratitis yet also drive corneal neovascularization and nerve damage that contribute to vision loss, illustrating how a single tissue can showcase both faces of neutrophil biology. We also examine the comparatively underappreciated role of neutrophils and neutrophil extracellular traps in helminth and protozoan infection, where they can both restrict parasite burden and drive collateral tissue injury. We conclude by evaluating strategies to modulate specific neutrophil states, rather than neutrophils as a whole, as an emerging therapeutic direction across bacterial, viral, fungal, and parasitic diseases, and by identifying gaps that single-cell and spatial approaches are positioned to close.