Microbial Proteases Drive Endothelial Barrier Disruption and DIC in Sepsis Pathogenesis

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, remaining a leading cause of global mortality. While host inflammatory pathways are extensively studied, the critical contribution of bacterial proteases to sepsis pathogenesis is often overlooked. Current therapeutic strategies often fall short because they primarily target host responses, neglecting direct microbial virulence factors that severely compromise vascular integrity. Understanding these bacterial mechanisms, particularly their impact on the vascular endothelium and coagulation cascades, is crucial for developing more effective interventions.

This review synthesizes existing mechanistic insights into how bacterial proteases contribute to sepsis pathogenesis. It examines experimental models used to study these proteases, discusses current diagnostic challenges, and explores emerging protease-targeted therapeutic strategies. The authors focused on key microbial proteases such as EspP, Protease IV, LasB, and SpeB, analyzing their direct effects on the vascular endothelium, glycocalyx, and coagulation pathways by summarizing findings from various preclinical studies.

Microbial proteases act as potent virulence factors, directly targeting the vascular endothelium and disrupting its integrity. They achieve this by cleaving junctional proteins, degrading the protective glycocalyx, and inactivating crucial anticoagulant molecules. This combined structural and functional damage leads to profound endothelial barrier failure and subsequent vascular leakage. Furthermore, these proteases directly degrade key coagulation factors such as fibrinogen, factor V, factor VIII, and thrombin, significantly contributing to the progression toward disseminated intravascular coagulation (DIC). Beyond direct endothelial damage, bacterial proteases also exacerbate inflammation by increasing inflammatory cytokine release, degrading complement components, and driving overall thrombo-inflammatory dysregulation. Specific proteases like EspP, Protease IV, LasB, and SpeB have been identified as key players in these destructive processes. > These microbial proteases directly degrade critical coagulation factors, including fibrinogen, factor V, factor VIII, and thrombin, accelerating DIC progression in sepsis.