Tuberculosis (TB) is the world’s leading bacterial cause of death. Effective treatment currently requires a minimum of 4 drugs taken for at least 6 months. While these drugs kill the TB causing bacteria (Mtb), they do not directly resolve the inmmunopathology associated with morbidity. Immunomodulatory agents that not only enhance an individual’s ability to kill Mtb but also help heal lung pathology could be used as adjuncts to current therapies to improve treatment outcome. Phenylbutyrate (PBA) has been in clinical use for more than 30 years to treat a range of conditions. It has also been shown to synergise with vitamin D to induce cellular production of the anti-Mtb peptide, cathelicidin. We investigated whether PBA and vitamin D synergistically kill Mtb in human macrophages and whether PBA has any independent effect on macrophages and Mtb. At concentrations that are achieved in plasma clinically, PBA inhibited Mtb growth. PBA also inhibited growth of Mtb in human macrophages via a cell-dependent mechanism, inducing the inflammasome pathway and antimicrobial lactoferrin. PBA also synergistically enhanced macrophage response to vitamin D and co-treatment further inhibited Mtb growth, when synergistically-induced cathelicidin was activated. PBA and vitamin D may therefore prove an effective combinatorial adjunct therapy for tuberculosis.
Vyšlo v časopise: Phenylbutyrate Is Bacteriostatic against and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D₃. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005007 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005007
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