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, but less information is available regarding the role and mechanisms of action of non­bactericidal AMPs in sepsis. Herein, a novel β-sheet cathelicidin antimicrobial peptide (Og-CATH) was identified from the frog Odorrana grahami. Intriguingly, Og-CATH showed no direct antimicrobial activity in vitro, but displayed prophylactic and therapeutic efficacy in Staphylococcus aureus, Enterobacteriaceae coli, or cecal ligation and puncture-induced septic mice. Neutrophils and monocytes/macrophages, but not T/B lymphocytes, were required for the protective efficacy of Og-CATH in mice. Og-CATH did not exhibit a direct chemoattractant effect on phagocytes, but it promoted macrophages and neutrophils trafficking to the infection site via chemokines secreted by P2X7 receptor-activated macrophages, and augmented their oxygen-independent bacterial killing functions via the enhancement of phagocytosis and neutrophils degranulation. Of note, Og-CATH also inhibited the production of tissue factor, a potent initiator of the extrinsic coagulation cascade, and up-regulated the expression of activated protein C, a physiological anticoagulant both in endothelial cells and in mice, which contribute to the reduction of pulmonary fibrin deposition and thrombosis in mice. Further investigation revealed that Og-CATH targeted the myeloid differentiation protein 2 (MD2), and inhibited the LPS-induced MyD88 recruitment to TLR4 in endothelial cells, thus attenuating endothelial barrier dysfunction during sepsis. Our data indicated that Og-CATH provides protective effects against sepsis through regulation of phagocytes and endothelial functions. These findings enrich our understanding of the anti-infection mechanism of non­bactericidal AMPs, and show that Og-CATH is an excellent candidate for further therapeutic development of sepsis.