A new target for host-directed therapy against TB infection

项目总结 结核病(TB)仍然是一个主要的全球健康问题，约有900万新结核病病例和 全球每年有近130万人死于结核病。耐药结核分支杆菌(Mtb) 使结核病成为当前抗结核分枝杆菌治疗的一个更加困难的挑战。结核分枝杆菌感染的持续性 巨噬细胞是通过抑制宿主免疫反应来调节的。免疫机制研究进展 然而，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 蛋白，单核细胞趋化蛋白诱导蛋白1(MCPIP1)就是这样一种结核分枝杆菌免疫逃逸蛋白。 巨噬细胞对炎性刺激如肿瘤坏死因子、白介素1、β和脂多糖有快速诱导作用。 MCPIP1缺陷小鼠表现出复杂的表型，包括自身免疫性疾病和严重的 炎症反应。MCPIP1抑制几种促炎细胞因子(包括IL-1、IL-6和IL-12)， 对T细胞的激活起到刹车的作用。到目前为止，MCPIP1已经被我们和其他人证明是一种 负性调节因子在控制炎症和维持体内平衡中的作用。然而，它在很大程度上仍然 尚不清楚MCPIP1是否影响结核杆菌复制或参与控制结核病的激活。我们最近做了 发现通过气雾剂途径感染Mtb的MCPIP1基因敲除小鼠显著减少了 与野生型小鼠的细菌负荷比较，以及MCPIP1在小鼠肺中的表达增加 WT小鼠。有趣的是，在活动性结核的干酪性肉芽肿中，MCPIP1的mRNA水平显著升高 患者肺实质较正常肺实质明显增多。此外，MCPIP1的mRNA水平也显著增加。 患有活动性和反应性结核病的恒河猴以及患有潜伏性结核病的恒河猴的肺。根据我们的发现， 我们认为，强毒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。在本申请中，我们建议(1)了解 Mtb诱导的MCPIP1和随后对Mtb感染的影响；(2)确定巨噬细胞在体内的作用- 衍生的MCPIP1在防止分枝杆菌生长和宿主翻译潜力的最佳控制中- 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避和 MCPIP1靶向治疗结核分枝杆菌感染的潜力 分枝杆菌多药耐药菌株感染。

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.