Journal Article

Treatment of Mycobacterium tuberculosis-Infected Macrophages with Poly(Lactic-Co-Glycolic Acid) Microparticles Drives NFκB and Autophagy Dependent Bacillary Killing

O’Sullivan, Mary P., Keane, Joseph, Lawlor, Ciaran, O’Connor, Gemma, Gallagher, Paul J., O’Leary, Seonadh, Cryan, Sally-Ann

2016

Overview

The emergence of multiple-drug-resistant tuberculosis (MDR-TB) has pushed our available repertoire of anti-TB therapies to the limit of effectiveness. This has increased the urgency to develop novel treatment modalities, and inhalable microparticle (MP) formulations are a promising option to target the site of infection. We have engineered poly(lactic-co-glycolic acid) (PLGA) MPs which can carry a payload of anti-TB agents, and are successfully taken up by human alveolar macrophages. Even without a drug cargo, MPs can be potent immunogens; yet little is known about how they influence macrophage function in the setting of Mycobacterium tuberculosis (Mtb) infection. To address this issue we infected THP-1 macrophages with Mtb H37Ra or H37Rv and treated with MPs. In controlled experiments we saw a reproducible reduction in bacillary viability when THP-1 macrophages were treated with drug-free MPs. NFκB activity was increased in MP-treated macrophages, although cytokine secretion was unaltered. Confocal microscopy of immortalized murine bone marrow-derived macrophages expressing GFP-tagged LC3 demonstrated induction of autophagy. Inhibition of caspases did not influence the MP-induced restriction of bacillary growth, however, blockade of NFκB or autophagy with pharmacological inhibitors reversed this MP effect on macrophage function. These data support harnessing inhaled PLGA MP-drug delivery systems as an immunotherapeutic in addition to serving as a vehicle for targeted drug delivery. Such \"added value\" could be exploited in the generation of inhaled vaccines as well as inhaled MDR-TB therapeutics when used as an adjunct to existing treatments.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Animals / Antigens / Apoptosis / Autophagy / Autophagy - drug effects / Bioengineering / Biology and Life Sciences / Bone marrow / Caspases - metabolism / Cell death / Cell Death - drug effects / Cell Death - immunology / Cell Line / Clinical medicine / Confocal microscopy / Cryan, Joseph / Cytokines / Cytokines - biosynthesis / Cytotoxicity, Immunologic - drug effects / Drug delivery / Drug delivery systems / Drug resistance / FDA approval / Formulations / Glycolic acid / Humans / Immunotherapy / Infections / Lactic Acid - administration & dosage / Lungs / Macrophages / Macrophages - drug effects / Macrophages - microbiology / Macrophages - physiology / Medicine / Medicine and Health Sciences / Mice / Microparticles / Microscopy / Multidrug resistance / Mycobacterium tuberculosis / Mycobacterium tuberculosis - immunology / NF-kappa B - metabolism / NF-κB protein / Phagocytosis / Pharmaceuticals / Pharmacology / Pharmacy / Polyglycolic Acid - administration & dosage / Polylactic Acid-Polyglycolic Acid Copolymer / Polylactide-co-glycolide / Tuberculosis / Vaccines / Viability