Coussens Anna K, Wilkinson Robert J, Martineau Adrian R
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease & Molecular Medicine, University of Cape Town, South Africa; Division of Mycobacterial Research, MRC National Institute of Medical Research, London, United Kingdom.
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease & Molecular Medicine, University of Cape Town, South Africa; Department of Medicine, Imperial College London, London, United Kingdom; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
PLoS Pathog. 2015 Jul 2;11(7):e1005007. doi: 10.1371/journal.ppat.1005007. eCollection 2015 Jul.
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 (0.4-4 mM) 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)D3 during infection and synergistically inhibit intracellular Mtb growth. PBA inhibited Mtb growth in broth with an MIC99 of 1 mM, which was reduced to 0.25 mM 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)D3 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)D3 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)D3 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.
辅助性维生素D治疗肺结核可增强炎症消退，但对细菌清除的作用较小。4-苯基丁酸钠（PBA）已在临床上用于多种病症，并已证明可与维生素D代谢物协同作用，上调抗菌肽（CAMP）的表达。我们研究了临床可达到的PBA血浆浓度（0.4-4 mM）是否直接影响结核分枝杆菌（Mtb）的生长以及人类巨噬细胞和外周血单核细胞对感染的反应。我们还测试了PBA在感染期间增强维生素D代谢物25(OH)D3的免疫调节作用并协同抑制细胞内Mtb生长的能力。PBA在肉汤中抑制Mtb生长，MIC99为1 mM，通过降低pH可降至0.25 mM。在人类巨噬细胞感染期间，PBA处理以剂量依赖性方式限制Mtb摄取、吞噬受体表达和细胞内生长。PBA独立调节CCL趋化因子分泌，并诱导抗菌乳铁蛋白（LTF）、抗炎蛋白C（PROC）以及NLRP3炎性小体途径内多个基因的表达。PBA与25(OH)D3联合处理可协同调节众多维生素D反应基因的表达，包括CAMP、CYP24A1、CXCL10和IL-37。这种协同效应依赖于MAPK信号传导，而PBA对LTF、PROC和NLRP3的作用不依赖于MAPK。在人类巨噬细胞的PBA和25(OH)D3联合处理期间，在没有外源性蛋白酶3（PR3）激活抗菌肽的情况下，Mtb生长限制主要由PBA的作用主导，而添加PR3可增强25(OH)D3和PBA联合处理对生长的限制作用。这表明PBA增强了人类巨噬细胞维生素D介导的抗菌肽依赖性Mtb生长限制，并独立诱导抗菌和抗炎作用。因此，通过宿主导向和细菌导向机制，PBA和维生素D可能被证明是一种有效的结核病联合辅助治疗方法，既能解决免疫病理学问题，又能增强细菌清除。
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