Low-Density Neutrophil Levels Are Correlated with Sporotrichosis Severity: Insights into Subcutaneous Fungal Infection

Abstract

Low-density neutrophils (LDNs) constitute a distinct subset of neutrophils among PBMCs. They are key mediators in systemic infections, amplifying inflammatory responses and potentially influencing disease severity and chronicity. However, their roles in subcutaneous fungal infections have not been previously investigated. In this study, we observed increased neutrophil counts in the blood and tissues of patients with sporotrichosis through automated blood analysis, histology, and immunohistochemistry. In addition, we found elevated granulocyte colony-stimulating factor levels by ELISAs. Flow cytometry analysis revealed a significant increase in CD16+CD66b+ LDNs compared with that in healthy controls. In vitro stimulation with Sporothrix globosa induced LDN generation. We observed positive correlations of LDN frequency with levels of CRP and myeloperoxidase. Conversely, granulocyte colony-stimulating factor levels were negatively correlated with LDN frequency. LDNs exhibited a combined mature/immature phenotype. Notably, transcriptomic analysis showed downregulation of pro-inflammatory signaling pathways in LDNs; functional assays also demonstrated reduced phagocytosis, ROS production, and neutrophil extracellular trap formation after stimulation with Sporothrix globosa. Degranulation did not exhibit significant changes, suggesting that LDNs constitute an impaired subpopulation. Our findings in the context of subcutaneous fungal infections indicate that LDN levels are significantly elevated in sporotrichosis and positively correlated with disease severity.