Laboratory of Mycobacterial Immunity and Pathogenesis, the Public Health Research Institute (PHRI) at the University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, United States of America.
PLoS Pathog. 2011 Sep;7(9):e1002262. doi: 10.1371/journal.ppat.1002262. Epub 2011 Sep 15.
Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment.
结核病（TB）的治疗受到实现治愈所需的长期抗生素治疗的阻碍。这种缓慢的反应部分归因于较少代谢活跃的结核分枝杆菌（Mtb）亚群能够抵抗当前抗结核药物的杀伤能力。我们使用免疫调节方法，用磷酸二酯酶 4（PDE4）抑制剂 CC-3052 抑制肿瘤坏死因子α（TNF-α）的产生，通过增加巨噬细胞内的 cAMP 来增强细胞内的 cAMP，以检查宿主与病原体之间的相互作用在感染结核分枝杆菌的兔子中用异烟肼（INH）治疗期间。基于 DNA 微阵列，CC-3052 治疗感染结核分枝杆菌的兔子期间宿主基因表达的变化支持 PDE4 抑制与固有免疫反应的特定下调之间的联系。与未治疗的兔子相比，用 CC-3052 治疗的感染兔子的肺部宿主基因表达的总体模式与体外静止结核分枝杆菌感染的巨噬细胞中描述的相似，表明巨噬细胞的激活不足。这些宿主免疫的改变与许多与代谢向休眠转变相关的结核分枝杆菌基因的相应下调有关。此外，用 CC-3052 和 INH 治疗导致与 INH 细菌反应相关的一些基因的表达降低。重要的是，与单独用 INH 治疗的兔子相比，用 CC-3052 治疗感染的兔子与结核分枝杆菌抵抗 INH 杀伤的能力降低有关，这表现在联合治疗动物的肺部中细菌清除率提高。我们的研究结果表明，宿主免疫反应的变化会导致结核分枝杆菌基因表达的变化，从而改变细菌对抗菌药物的反应性。这些发现为探索使用 PDE4 抑制剂辅助免疫调节增强现有抗结核治疗效果的潜力提供了依据。
