Animals, Autophagy, Caspases, Cell Death, Cell Line, Cytokines, Cytotoxicity, Immunologic, Humans, Lactic Acid, Macrophages, Mice, Mycobacterium tuberculosis, NF-kappa B, Phagocytosis, Polyglycolic Acid
: This work was supported by the Irish Health Research Board (http://www.hrb.ie/home/) under grant RP/2006/152 and HRB HRAPOR/2012/ 43 (SAC), HRB CSA/2012/16 and the Royal City of Dublin Hospital Trust, (JK) and Science Foundation Ireland (http://www.sfi.ie/) 08/RFP/BMT1689 (MOS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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.
Pharmacy and Pharmaceutical Sciences
Lawlor C, O'Connor G, O'Leary S, Gallagher PJ, Cryan SA, Keane J, O'Sullivan MP. Treatment of Mycobacterium tuberculosis-Infected Macrophages with Poly(Lactic-Co-Glycolic Acid) Microparticles Drives NFκB and Autophagy Dependent Bacillary Killing. PLoS One. 2016;11(2):e0149167.
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