Microbial proteases and endothelial barrier disruption in sepsis: A neglected nexus

Sepsis is a life-threatening condition characterized by dysregulated host responses to infection and remains a leading cause of mortality globally. While host inflammatory pathways have been extensively studied, the contribution of bacterial proteases to sepsis pathogenesis remains underappreciated. Emerging evidence indicates that bacterial proteases act as potent virulence factors that directly target the vascular endothelium by cleaving junctional proteins, degrading the glycocalyx, inactivating anticoagulant molecules and degrading key coagulation factors such as fibrinogen, factor V, factor VIII and thrombin. This combined structural and functional damage leads to endothelial barrier failure, vascular leakage and progression toward disseminated intravascular coagulation (DIC). Additionally, bacterial proteases increase inflammatory cytokine release, degrade complement components and drive thrombo-inflammatory dysregulation. This review summarizes mechanistic insights into key microbial proteases such as EspP, Protease IV, LasB and SpeB, highlighting experimental models, diagnostic challenges and emerging protease-targeted therapeutic strategies with implications for improving sepsis outcomes.