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Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammation but has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is in clinical use for a range of conditions and has been shown to synergise with vitamin D metabolites to upregulate cathelicidin antimicrobial peptide ( CAMP ) expression. We investigated whether clinically attainable plasma concentrations of PBA (0.4-4mM) directly affect  Mycobacterium tuberculosis  ( Mtb ) growth and human macrophage and PBMC response to infection. We also tested the ability of PBA to enhance the immunomodulatory actions of the vitamin D metabolite 25(OH)D 3  during infection and synergistically inhibit intracellular  Mtb  growth. PBA inhibited  Mtb  growth in broth with an MIC 99  of 1mM, which was reduced to 0.25mM by lowering pH. During human macrophage infection, PBA treatment restricted  Mtb  uptake, phagocytic receptor expression and intracellular growth in a dose-dependent manner. PBA independently regulated CCL chemokine secretion and induced expression of the antimicrobial  LTF  (lactoferrin), the anti-inflammatory  PROC  (protein C) and multiple genes within the NLRP3 inflammasome pathway. PBA co-treatment with 25(OH)D 3  synergistically modulated expression of numerous vitamin D-response genes, including  CAMP ,  CYP24A1 ,  CXCL10  and  IL-37 . This synergistic effect was dependent on MAPK signalling, while the effect of PBA on  LTF ,  PROC  and  NLRP3  was MAPK-independent. During PBA and 25(OH)D 3  co-treatment of human macrophages, in the absence of exogenous proteinase 3 (PR3) to activate cathelicidin,  Mtb  growth restriction was dominated by the effect of PBA, while the addition of PR3 enhanced growth restriction by 25(OH)D 3  and PBA co-treatment. This suggests that PBA augments vitamin D–mediated cathelicidin-dependent  Mtb  growth restriction by human macrophages and independently induces antimicrobial and anti-inflammatory action. Therefore through both host-directed and bacterial-directed mechanisms PBA and vitamin D may prove an effective combinatorial adjunct therapy for tuberculosis to both resolve immunopathology and enhance bacterial clearance.

plos pathogens

Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D₃