Department of Microbiology and Immunology, Faculty of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan.
J Infect Chemother. 2011 Jun;17(3):302-17. doi: 10.1007/s10156-010-0177-y. Epub 2011 Jan 18.
The worldwide increase in the prevalence of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and new effective drugs are urgently needed. Information on the genome of Mycobacterium tuberculosis (MTB) and various mycobacterial virulence genes is leading to the identification of genes that code for new drug targets. Mycobacterium tuberculosis (MTB) is resistant to the antimicrobial mechanisms of host macrophages and can survive and replicate in macrophages for long periods, resulting in a persistent infection. Mycobacterial virulence factors suppress macrophage bactericidal functions partly via their downregulatory effects on the host antimicrobial cytokine networks, consisting of proinflammatory, immunopotentiating, and Th1-inducing cytokines. Thus, for the development of unique drugs that exhibit antimycobacterial action through novel mechanisms, it is reasonable to search for targets among bacterial genes encoding virulence factors which interfere with the host cytokine responses protective to mycobacterial pathogens. In this review, we discuss the profiles of cytokine networks related to host resistance to mycobacteria, including the mechanisms of downregulation of host antimycobacterial immunity due to immunosuppressive cytokines, which are occasionally induced in the advanced stages of TB. We also highlight the development of antituberculous drugs based on bacterial virulence factors interfering with the host antimycobacterial cytokine network.
全球范围内结核病（TB）的患病率上升，尤其是耐多药结核病和广泛耐药结核病，这是一个重要的全球健康关注点，急需新的有效药物。关于结核分枝杆菌（MTB）基因组和各种分枝杆菌毒力基因的信息，正在导致识别新的药物靶点的基因。结核分枝杆菌（MTB）对宿主巨噬细胞的抗菌机制具有抗性，能够在巨噬细胞中长期存活和复制，导致持续感染。分枝杆菌毒力因子通过下调宿主抗菌细胞因子网络来部分抑制巨噬细胞的杀菌功能，该网络由促炎、免疫增强和 Th1 诱导细胞因子组成。因此，为了开发通过新机制发挥抗分枝杆菌作用的独特药物，有理由在编码干扰宿主对抗分枝杆菌病原体的细胞因子反应的毒力因子的细菌基因中寻找靶标。在这篇综述中，我们讨论了与宿主对分枝杆菌的抗性相关的细胞因子网络的特征，包括由于在结核病的晚期偶尔诱导的免疫抑制细胞因子而导致宿主抗分枝杆菌免疫下调的机制。我们还强调了基于干扰宿主抗分枝杆菌细胞因子网络的细菌毒力因子开发抗结核药物。
