Characterizing a low-density neutrophil gene signature in acute and chronic infections and its impact on disease severity

Abstract Low-density neutrophils (LDNs) or polymorphonuclear myeloid-derived suppressor cells are involved in the pathogenesis of cancer, autoimmune, and infectious diseases. They are crucial in the host response to invading pathogens, especially during acute illness, and are associated with poor prognosis in many infectious diseases. However, their gene expression profile and contribution to disease outcomes are not well described. We conducted a meta-analysis of gene expression datasets from peripheral blood mononuclear cells (PBMCs), focusing on patients with viral and bacterial infections. We identified a consensus set of 2,798 differentially expressed genes. Among these, 49 genes were commonly found in both the neutrophil degranulation pathway and the granule lumen-specific community. To validate this signature, we evaluated its expression in RNA-seq datasets, finding consistent upregulation of 24 genes in severe infections, 17 of them overlapped with genes overexpressed in CD16int cells. We also investigated the abundance of LDN-related proteins in a PBMC proteomics dataset from a cohort of sepsis and septic shock patients. Out of the 17 genes analyzed, 13 corresponding proteins were identified, 10 of which demonstrated significantly higher abundance in sepsis and septic shock patients compared with healthy controls. In conclusion, our study identified a pattern of 17 upregulated LDN genes, common to PBMC transcriptome and RNA-seq, and upregulated in CD16int, associated with acute infections and severe clinical outcomes, marking the first time these genes have been collectively presented as a potential signature of LDNs in relation to disease severity. Further research with prospective cohorts is needed to validate this LDN signature and explore its clinical implications.