Author(s):
Silva, João P. ; Gonçalves, Carine ; Costa, C. ; Sousa, Jeremy ; Silva-Gomes, Rita ; Castro, António G. ; Pedrosa, Jorge ; Appelberg, Rui ; Gama, F. M.
Date: 2016
Persistent ID: https://hdl.handle.net/1822/41895
Origin: RepositóriUM - Universidade do Minho
Project/scholarship:
info:eu-repo/grantAgreement/FCT/5876-PPCDTI/126270/PT
;
info:eu-repo/grantAgreement/FCT/5876/147337/PT;
info:eu-repo/grantAgreement/FCT/COMPETE/126270/PT;
Subject(s): Antimicrobial peptide; Macrophages; Infectious diseases; Cathelicidin; Mycobacteria; Science & Technology
Description
uberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, recently joined HIV/AIDS on the top rank of deadliest infectious diseases. Low patient compliance due to the expensive, long-lasting and multi-drug standard therapies often results in treatment failure and emergence of multi-drug resistant strains. In this scope, antimicrobial peptides (AMPs) arise as promising candidates for TB treatment. Here we describe the ability of the exogenous AMP LLKKK18 to efficiently kill mycobacteria. The peptide's potential was boosted by loading into self-assembling Hyaluronic Acid (HA) nanogels. These provide increased stability, reduced cytotoxicity and degradability, while potentiating peptide targeting to main sites of infection. The nanogels were effectively internalized by macrophages and the peptide presence and co-localization with mycobacteria within host cells was confirmed. This resulted in a significant reduction of the mycobacterial load in macrophages infected in vitro with the opportunistic M. avium or the pathogenic M. tuberculosis, an effect accompanied by lowered pro-inflammatory cytokine levels (IL-6 and TNF-). Remarkably, intra-tracheal administration of peptide-loaded nanogels significantly reduced infection levels in mice infected with M. avium or M. tuberculosis, after just 5 or 10 every other day administrations. Considering the reported low probability of resistance acquisition, these findings suggest a great potential of LLKKK18-loaded nanogels for TB therapeutics.
This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER- 006684). The authors also acknowledge the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462). The authors thank Dr. Hugo Osório (Proteomics Lab at I3S – Institute for Health Research and Innovation, Porto, Portugal) for the MALDI-ToF analysis. JPS acknowledges FCT for the financial support provided by grant SFRH/BPD/64958/2010.
