A non-bactericidal antimicrobial peptide provides protective effect against bacterial sepsis via regulation of antimicrobial immunity and vascular endothelial functions

The anti-infective properties of bactericidal antimicrobial peptides (AMPs) have been extensively studied, yet the functions and mechanisms of non-bactericidal AMPs in sepsis remain poorly understood. In this study, a novel β-sheet cathelicidin peptide, named Og-CATH, was identified from the skin of Odorrana grahami. Although Og-CATH showed no detectable direct antimicrobial activity in vitro, it provided both prophylactic and therapeutic protection in mouse models of sepsis induced by Staphylococcus aureus, Escherichia coli, or cecal ligation and puncture. This protection depended on neutrophils and monocytes/macrophages, but not T or B lymphocytes. Og-CATH did not directly chemoattract phagocytes. Instead, it stimulated P2X7 receptor-dependent chemokine release from macrophages, thereby promoting macrophage and neutrophil trafficking to sites of infection. Og-CATH also enhanced oxygen-independent bacterial clearance by increasing phagocytosis and neutrophil degranulation. In parallel, Og-CATH suppressed tissue factor production, a major trigger of the extrinsic coagulation cascade, and increased activated protein C expression in endothelial cells and mice, thereby reducing pulmonary fibrin deposition and thrombosis. Mechanistically, Og-CATH targeted myeloid differentiation protein 2 (MD2) and inhibited lipopolysaccharide (LPS)-induced recruitment of MyD88 to TLR4 in endothelial cells, thus preserving endothelial barrier integrity during sepsis. These findings identify Og-CATH as a non-bactericidal AMP that protects against sepsis by coordinating phagocyte recruitment, antibacterial effector activity, coagulation control, and endothelial stabilization. Og-CATH therefore represents a promising immunomodulatory candidate for further therapeutic development against sepsis.