Treatment of Mycobacterium tuberculosis-Infected Macrophages with PolyLactic-Co-Glycolic Acid Microparticles Drives NFκB and Autophagy Dependent Bacillary KillingReportar como inadecuado




Treatment of Mycobacterium tuberculosis-Infected Macrophages with PolyLactic-Co-Glycolic Acid Microparticles Drives NFκB and Autophagy Dependent Bacillary Killing - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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 polylactic-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.



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

Fuente: http://plos.srce.hr/



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