Plasma extracellular vesicle proteomic signatures are associated with immunothrombosis and homeostatic dysregulation in septic shock.

Abstract

Sepsis and septic shock are life-threatening conditions involving severe immune, coagulation, and organ dysfunction. Extracellular vesicles (EVs) circulate during systemic inflammation and carry molecular cargo reflecting pathophysiology; however, differences in plasma EV proteomic profiles between sepsis and septic shock remain incompletely characterized. In this exploratory cross-sectional study, we characterized SEC-enriched plasma EV preparations from patients with sepsis (n = 7), septic shock (n = 7), and healthy controls (n = 7) using label-free shotgun proteomics. Differential proteomic, functional enrichment, and protein-protein interaction analyses revealed distinct molecular patterns and biological networks across clinical groups. Proteins differing between patients and healthy controls were enriched in innate immune responses, neutrophil degranulation, complement/coagulation pathways, and cell adhesion. Furthermore, direct comparison between sepsis and septic shock highlighted specific patterns in the septic shock group related to homeostatic processes, biological regulation, and tissue remodeling. Overall, our findings indicate that plasma EV-enriched preparations exhibit distinct proteomic patterns associated with sepsis and septic shock, including proteins mapping to immune, coagulation, and homeostasis-related processes. These results provide an exploratory proteomic framework for investigating EV-associated molecular changes between clinical groups, while functional studies and validation in larger cohorts will be required to determine their biological and clinical relevance. SIGNIFICANCE: Sepsis is a heterogeneous clinical syndrome in which the molecular changes associated with increasing disease severity remain incompletely characterized. In this exploratory study, we used label-free shotgun proteomics to characterize Size Exclusion Chromatography-enriched plasma extracellular vesicle preparations from healthy controls and patients with sepsis or septic shock. The analysis identified group-associated protein patterns and biological processes related to innate immunity, neutrophil responses, complement, coagulation, and homeostatic regulation. Rather than establishing a functional role for EVs in these processes, our findings show that EV-associated proteomic profiles contain molecular information associated with clinical disease severity. These results provide candidate molecular patterns and biological hypotheses for validation in larger independent cohorts and for subsequent functional investigation.

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