Systemic Administration of Avian Defensin 7: Distribution, Cellular Target, and Antibacterial Potential in Mice.

Geoffrey Bailleul,Isabelle Virlogeux-Payant,Isabelle Lantier,Philippe Velge,Agnès Wiedemann,Florence B Gilbert,Rodrigo Guabiraba,Anne-Christine Lalmanach,Angélina Trotereau,Jérôme Trotereau,Catherine Schouler

doi:10.3389/fmicb.2019.00541

Geoffrey Bailleul, Isabelle Virlogeux-Payant + Show 9 more

Open Access

https://doi.org/10.3389/fmicb.2019.00541

Copy DOI

Abstract

Defensins are natural antimicrobial peptides. The avian beta-defensin AvBD7 isolated from the chicken bone marrow possess broad antibacterial spectrum and strong resistance to proteolysis. However, its ability to fight systemic infections of major concern for public health, such as salmonellosis, is unknown. As a first approach, fluorescence labeling of AvBD7 allowed to track its systemic distribution after intraperitoneal injection in mice using whole body live imaging. It was associated to peritoneal cells and to deeper organs such as the liver. In the next step, the use of labeled AvBD7 allowed to observe its interaction with murine macrophages in culture. After incubation, it was able to penetrate inside the cells through an endocytosis-like mechanism. Furthermore, natural AvBD7 contributed to the control of intracellular multiplication of a multidrug resistant Salmonella strain, after incubation with infected macrophages. Finally, administration in a model of systemic lethal Salmonella infection in mice led to significant improvement of mouse survival, consistently with significant reduction of the liver bacterial load. In conclusion, the results reveal a hitherto unknown intracellular antibacterial effect of AvBD7 in Salmonella target cells and support AvBD7 as a candidate of interest for the treatment of infectious diseases caused by multidrug-resistant pathogenic Enterobacteriaceae.

Highlights

Host defense peptides are important antimicrobial components of animal’s innate immunity
In many species of gram-negative bacteria, the charge on the outer membrane is modulated by the two-component system PhoPQ regulon affecting cationic antimicrobial peptide sensitivity through modulation of the PmrA regulon, which controls a set of genes that mediate decoration of the outer membrane with the positively charged moieties ethanolamine and 4-aminoarabinose (Gunn et al, 2000)
Times for image acquisition are indicated on each image. (A) Mice imaged on left lateral view. (B) Pelleted peritoneal cells collected from control or fluorescent AvBD7-injected mice. (C) Mice imaged on left lateral view, hiding the kidneys area. (D) Organs imaged ex vivo (K, kidneys; S, spleen; L, liver; MLN, mesenteric lymph node). (E) Quantification of AvBD7 fluorescence by comparison to that of the free dye fluorescence in organs collected post i.p. injection in a sacrificed animal at three indicated times

Summary

Introduction

Host defense peptides are important antimicrobial components of animal’s innate immunity. The cross-resistance of laboratory-selected mutants to other peptides seems to be limited (Samuelsen et al, 2005), and the importance of immunomodulatory properties of these peptides, which would not be affected by antimicrobial resistance, has been increasingly recognized (Hancock et al, 2016) Taken together, these properties place defensins as a potential therapeutic solution alternative or complementary to conventional antibiotics. In spite of an abundant database of antimicrobial peptides, only a few of them have reached phase II–III clinical trials and mainly for topical applications (Mahlapuu et al, 2016) This can be due to a low stability of the peptides under physiopathological conditions and/or to their weak systemic bio-distribution in the case of infections targeting remote organs

Objectives

Methods

Results

Conclusion