Sepsis is a major cause of mortality worldwide, with modest improvements in the last decades. A significant challenge for the outcome improvement lies in the marked disease heterogeneity among patients. Stratifying patients into distinct endotypes is needed for more precise interventions. This study investigates the transcriptomic landscape of sepsis patients stratified by their inflammatory endotype.

We obtained peripheral blood mononuclear cells from 125 sepsis patients (as per Sepsis-2 criteria) and 299 volunteers as part of the Functional Genomics in Severe Infections project (FUSE). RNA sequencing was conducted to identify differentially expressed genes and enriched pathways. We compared the transcriptomic profiles of previously defined “high-” and “low-inflammatory” endotypes, obtained through targeted inflammatory proteomics.

Sepsis was linked to widespread transcriptional changes in innate immunity genes, notably those linked to phagocytosis and antimicrobial peptides, alongside paradoxical reduced NK cell-mediated immunity. Adaptive immunity genes, particularly those involved in T cell differentiation, were downregulated. Importantly, infection etiology and infection site had no discernible impact on gene expression profiles. In the “high-inflammatory” endotype, interferon-associated chemokines CXCL9 and CXCL10 were markedly upregulated at the transcription level in peripheral blood mononuclear cells, with concordant elevations in their circulating serum concentrations, as assessed by targeted proteomics and ELISA.

Immune dysregulation in sepsis is more driven by disease severity than infection site. The robust activation of the interferon-gamma-CXCL9-CXCL10 axis observed in the “high-inflammatory” endotype may present a promising target for personalized immunotherapies.