Abstract
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 (PopuCATH) from tree frog (Polypedates puerensis) did not't show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of PopuCATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. PopuCATH 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 PopuCATH significantly drove the leukocyte influx in both frogs and mice. In mice, PopuCATH 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 PopuCATH. PopuCATH did not directly act as chemoattractant for phagocytes, but PopuCATH obviously drove phagocyte migration when it was cultured with macrophages. PopuCATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65. PopuCATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, PopuCATH showed low side effects both in vitro and in vivo. Collectively, PopuCATH 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 PopuCATH to prevent bacterial infection.
Highlights
Antimicrobial peptides (AMPs) are a wide array of gene-e ncoded small defensive molecules that have been identified from prokaryotic to eukaryotic kingdoms, including bacteria, fungi, plantae, and animalia
Based on the structural characterisation, the mature peptides of cathelicidins can be distinguished into amphipathic α-h elical structure, beta-s heet structure, and structure enriched in specific amino acids like proline/arginine residues
Cathelicidins were initially characterised for their direct antimicrobial activity (Gennaro et al, 1989), which act as natural amino acid-based antibiotics with broad spectrum that directly target bacteria (Snoussi et al, 2018)
Summary
Antimicrobial peptides (AMPs) are a wide array of gene-e ncoded small defensive molecules that have been identified from prokaryotic to eukaryotic kingdoms, including bacteria, fungi, plantae, and animalia About 20 cathelicidins were identified from amphibians, including frog cathelicidins identified from Amolops loloensis (Hao et al, 2012), Paa yunnanensis (Wei et al, 2013), Rana catesbeiana (Ling et al, 2014), Limnonectes fragilis (Anura: Ranidae) (Yu et al, 2013), Microhyla heymonsivogt (Anura: Microhylidae) (Chai et al, 2021), Polypedates puerensis (Anura: Rhacophorinae) (Mu et al, 2017), (Anura: Dicroglossidae), toad cathelicidins identified from Duttaphrynus melanostictus (Gao et al, 2016), Bufo bufo gargarizans (Anura: Bufonidae) (Sun et al, 2015b), salamander cathelicidin identified from Tylototriton verrucosus (Mu et al, 2014), Andrias davidianus (Yang et al, 2017) (Caudata: Salamandridae), and others Most of these cathelicidins from frogs, toads, and salamanders exhibited direct antimicrobial activities with broad spectrum via dual bactericidal-immunomodulatory activities. Our study provides new insight for better understanding the anti-infective property and relative mechanism of non-b actericidal cathelicidin, and highlights a host-b ased immune defense regulator for preventing bacterial infection without drug-resistant risk
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