Tri-mannose grafting of chitosan nanocarriers remodels the macrophage response to bacterial infection

Juan Manuel Coya,Brigitte Gicquel,Inés Serrano-Sevilla,Anne Biton,Jesus M De La Fuente,Laura De Matteis,Ludovic Tailleux,Marie-Agnès Dillies,Anne Danckaert,Alexandre Giraud-Gatineau

doi:10.1186/s12951-018-0439-x

Abstract

BackgroundInfectious diseases are still a leading cause of death and, with the emergence of drug resistance, pose a great threat to human health. New drugs and strategies are thus urgently needed to improve treatment efficacy and limit drug-associated side effects. Nanotechnology-based drug delivery systems are promising approaches, offering hope in the fight against drug resistant bacteria. However, how nanocarriers influence the response of innate immune cells to bacterial infection is mostly unknown.ResultsHere, we used Mycobacterium tuberculosis as a model of bacterial infection to examine the impact of mannose functionalization of chitosan nanocarriers (CS-NCs) on the human macrophage response. Both ungrafted and grafted CS-NCs were similarly internalized by macrophages, via an actin cytoskeleton-dependent process. Although tri-mannose ligands did not modify the capacity of CS-NCs to escape lysosomal degradation, they profoundly remodeled the response of M. tuberculosis-infected macrophages. mRNA sequencing showed nearly 900 genes to be differentially expressed due to tri-mannose grafting. Unexpectedly, the set of modulated genes was enriched for pathways involved in cell metabolism, particularly oxidative phosphorylation and sugar metabolism.ConclusionsThe ability to modulate cell metabolism by grafting ligands at the surface of nanoparticles may thus be a promising strategy to reprogram immune cells and improve the efficacy of encapsulated drugs.

Highlights

Infectious diseases are still a leading cause of death and, with the emergence of drug resistance, pose a great threat to human health
We previously reported the production of chitosan NCs (CS-NCs) with improved stability, by nanoemulsion with a chitosan hydrogel coating, and their use as an efficient drug delivery system for the antimicrobial agent bedaquiline [18, 19]
Chitosan NCs are efficiently internalized by Mφs in an actin cytoskeleton‐dependent manner We first evaluated the capacity of human Mφs to internalize CS-NCs

Summary

Introduction

Infectious diseases are still a leading cause of death and, with the emergence of drug resistance, pose a great threat to human health. Even more serious is the worldwide emergence of drug-resistant bacteria, Nanoparticles are an attractive approach to increase the efficacy of antibiotics and decrease drug side-effects [4, 5]. It was shown that nanoparticles are able to effectively target granuloma-like structures using transparent zebrafish embryos infected with Mycobacterium marinum as a model of TB infection, improving embryo survival and lowering bacterial load [7]. NCs have been recently used to improve BCG-vaccine immunogenicity by enhancing the innate immune response to BCG vaccination [17]

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Conclusion