A new target for host-directed therapy against TB infection

项目概要 结核病 (TB) 仍然是全球主要健康问题，新增结核病例约 900 万例， 全球每年有近 130 万人死于结核病。耐药结核分枝杆菌 (Mtb) 使得结核病成为当前抗结核病治疗面临的更加困难的挑战。结核分枝杆菌感染的持续存在 巨噬细胞通过抑制宿主免疫反应介导。免疫机制 然而，人们对 Mtb 的镇压仍然知之甚少。我们的初步数据表明一种新的 RNA 结合 单核细胞趋化蛋白诱导蛋白1（MCPIP1）就是这样一种用于结核分枝杆菌免疫逃避的蛋白。 MCPIP1 在巨噬细胞中快速诱导，以响应 TNF、IL-1β 和 LPS 等炎症刺激。 MCPIP1 缺陷小鼠会出现复杂的表型，包括自身免疫性疾病和严重的 炎症反应。 MCPIP1 抑制多种促炎细胞因子（包括 IL-1、IL-6 和 IL-12）， 并且还起到 T 细胞激活的刹车作用。到目前为止，MCPIP1 已被我们和其他人证明是 控制炎症和维持体内平衡的负调节因子。然而，它在很大程度上仍然 尚不清楚 MCPIP1 是否影响 Mtb 复制或参与 TB 激活的控制。我们最近有 发现通过气溶胶途径感染 Mtb 的 MCPIP1 敲除小鼠显着减少 与野生型小鼠相比，细菌负荷增加，并且肺部 MCPIP1 表达增加 WT小鼠。有趣的是，MCPIP1 mRNA 水平在活动性结核病的干酪肉芽肿中显着较高 患者肺实质较正常。此外，MCPIP1 mRNA水平也显着增加 患有活动性和反应性结核病以及潜伏性结核病的恒河猴的肺部。根据我们的发现， 我们提出，有毒力的结核分枝杆菌通过诱导 MCPIP1 来逃避宿主免疫攻击， 抑制抗结核免疫反应。在此应用中，我们建议（1）了解以下机制： Mtb 诱导 MCPIP1 及其对 Mtb 感染的后续影响； (2) 定义巨噬细胞的体内作用- 衍生的 MCPIP1 阻止分枝杆菌生长的最佳控制和宿主的转化潜力 定向治疗。这项研究的结果将使我们更好地了解结核病免疫逃逸和 MCPIP1 靶向治疗治疗 Mtb 感染的治疗潜力，特别是那些患者 感染了分枝杆菌的 MDR 染色。

PROJECT SUMMARY Tuberculosis (TB) remains a leading global health problem with about 9 million new tuberculosis cases and nearly 1.3 million TB-related deaths worldwide each year. Drug-resistant Mycobacterium tuberculosis (Mtb) makes TB an even more difficult challenge for current anti-Mtb therapy. Persistence of Mtb infection in macrophages is mediated by suppression of host immune responses. The mechanisms of immune suppression by Mtb, however, are still poorly understood. Our preliminary data indicate a new RNA-binding protein, monocyte chemotactic protein-induce protein 1 (MCPIP1) is such a protein for immune evasion of Mtb. MCPIP1 is rapidly induced in macrophages in response to inflammatory stimuli such as TNF, IL-1β and LPS. MCPIP1-deficient mice develop complex phenotypes, including autoimmune disorders and severe inflammatory responses. MCPIP1 inhibits several proinflammatory cytokines (including IL-1, IL-6 and IL-12), and also acts like a brake for T cell activation. So far, MCPIP1 has been shown by us and others to be a negative regulator in controlling inflammation and maintaining homeostasis. However, it remains largely unknown whether MCPIP1 affects Mtb replication or involves in control of TB activation. We have recently found that MCPIP1 knockout mice infected with Mtb via the aerosol route have a significant reduction of bacterial burden compared with wild type mice, along with an increase in MCPIP1 expression in lungs of the WT mice. Interestingly, MCPIP1 mRNA levels are significantly higher in caseous granulomas of active TB patients than normal lung parenchyma. Moreover, MCPIP1 mRNA levels are also significantly increased in lungs of rhesus macaques with active and reactive TB as well as those with latent TB. Based on our discovery, we propose that virulent Mycobacterium tuberculosis evades host immune attack by inducing MCPIP1 which suppresses anti-TB immune responses. In this application, we propose to (1) understand the mechanisms of MCPIP1 induction by Mtb and subsequent effects on Mtb infection; (2) define in vivo role of macrophage- derived MCPIP1 in preventing optimal control of mycobacterial growth and the translational potential for host- directed therapy. Results of this study will provide us a better understanding of TB immune evasion and therapeutic potential of MCPIP1-targeted therapy in treatment of Mtb infection, especially those patients infected with MDR stains of mycobacteria.