Hyper-activated low-density neutrophil-derived NGAL predicts fatal SFTS: a multi-cohort and single-cell study

PURPOSE: Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease with rapid progression and high mortality. This study aimed to assess the predictive power of serum neutrophil gelatinase-associated lipocalin (NGAL) for mortality risk and elucidate its cellular origin at the single-cell level. METHODS: In this retrospective multicenter study, we analyzed clinical data from 215 SFTS patients across three Chinese hospitals (152 in the training cohort and 63 in the external validation cohort). We further analyzed publicly available single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) from SFTS patients and healthy controls to investigate the cellular source of NGAL. RESULTS: Serum NGAL was identified as an independent risk factor for 14-day and 28-day all-cause mortality (P < 0.05). High NGAL levels were linearly associated with increased mortality and remained stable across various clinical subgroups. Crucially, unbiased scRNA-seq analysis revealed that the elevated NGAL (encoded by the LCN2 gene) primarily originated from low-density neutrophils (LDNs) that co-purified with PBMCs. These LCN2-expressing LDNs were highly enriched in non-survivors and exhibited a hyper-inflammatory, interferon-stimulated transcriptomic signature. CONCLUSION: Our findings establish serum NGAL as a robust early predictor of mortality risk in SFTS patients, with its elevation intrinsically linked to the pathogenic emergence of highly activated LDNs, providing novel insights into the immunopathology of fatal SFTS.