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The roles of bactericidal cathelicidins against bacterial infection have been extensively studied. However, the antibacterial property and mechanism of action of non-bactericidal cathelicidins are rarely known. Herein, a novel naturally occurring cathelicidin ( Popu CATH) from tree frog ( Polypedates puerensis ) did not show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of  Popu CATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice.  Popu CATH pretreatment also increased the survival rates of septic mice induced by a lethal dose of bacterial inoculation or cecal ligation and puncture (CLP). Intraperitoneal injection of  Popu CATH significantly drove the leukocyte influx in both frogs and mice. In mice,  Popu CATH rapidly drove neutrophil, monocyte/macrophage influx in mouse abdominal cavity and peripheral blood with a negligible impact on T and B lymphocytes, and neutrophils, monocytes/macrophages, but not T and B lymphocytes, were required for the preventive efficacy of  Popu CATH.  Popu CATH did not directly act as chemoattractant for phagocytes, but  Popu CATH obviously drove phagocyte migration when it was cultured with macrophages.  Popu CATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65.  Popu CATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally,  Popu CATH showed low side effects both in vitro and in vivo. Collectively,  Popu CATH acts as a host-based immune defense regulator that provides prophylactic efficacy against bacterial infection without direct antimicrobial effects. Our findings reveal a non-bactericidal cathelicidin which possesses unique anti-bacterial action, and highlight the potential of  Popu CATH to prevent bacterial infection.

A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx