The role of FENDRR in host defense against Mycobacterium tuberculosis infection

项目总结 结核分枝杆菌(M.tb)是一种引起人类结核病的细胞内细菌病原体。 结核病仍然是一个主要的全球公共卫生威胁。每年，大约有1000万个活跃的 全球结核病病例和140万人死亡。宿主与结核分枝杆菌相互作用的机制仍有待进一步研究 已定义。长非编码RNA(LncRNAs)是长度超过200个核苷酸的非编码转录本。作为回应 对于细菌感染，哺乳动物细胞产生丰富的lncRNA来介导宿主和病原体的相互作用， 哪些对东道主防御有利或不利。关于这方面的研究报道非常有限 宿主lncRNAs在结核分枝杆菌感染应答中的作用然而，越来越多的证据表明，宿主LncRNA 参与宿主防御宿主细胞中的微生物感染。我们的长期目标是澄清 宿主lncRNA调节巨噬细胞抗结核分枝杆菌应答的基本机制及研究 宿主lncRNAs作为新的宿主导向治疗结核病的潜在应用。我们的初步数据 提示结核分枝杆菌感染可诱导宿主非编码发育调控因子lncRNA的表达 RNA(Fendrr)，在体外和体内的小鼠和人巨噬细胞中。此外，Fendrr-击倒 在细胞培养中促进小鼠和人巨噬细胞中结核分枝杆菌的生长。此外，Fendrr与 宿主铁反应元件结合蛋白1(Irp1)及其下调宿主microRNA miR-214的表达 结核分枝杆菌感染后的巨噬细胞。我们假设Fendrr通过控制 通过干扰铁反应蛋白Irp1和上调抗结核分枝杆菌抗体来提高细胞内铁的利用率 Zust Homolog 1蛋白增强子(EZH1)通过与宿主microRNA miR-214竞争。我们将测试 我们的假设使用了小鼠和人的巨噬细胞培养，以及小鼠的结核病模型。我会瞄准的 探讨结核分枝杆菌通过TLR2-MyD88-p38-C/EBPβ轴诱导FendrR表达的机制。 AIM II将确定Fendrr产生抗结核分枝杆菌反应的机制。AIM III将评估 Fendrr在小鼠结核病模型中的功能作用和作用机制。建议进行的研究 将揭示一个由宿主lncRNA Fendrr介导的新的抗结核分枝杆菌途径。

PROJECT SUMMARY Mycobacterium tuberculosis (M.tb) is an intracellular bacterial pathogen that causes tuberculosis in humans. Tuberculosis remains a major global public health threat. Annually, there are approximately 10 million active tuberculosis cases and 1.4 million deaths worldwide. The mechanism of host-M.tb interactions remains to be defined. Long noncoding RNAs (lncRNAs) are noncoding transcripts longer than 200 nucleotides. In response to bacterial infections, mammalian cells produce abundant lncRNAs to mediate host-pathogen interactions, which are beneficial or detrimental to host defense. A very limited number of studies have been reported on the role of host lncRNAs in the response to M.tb infection. However, increasing evidence indicates that host lncRNAs are engaged in the host defense against microbial infection in host cells. Our long-term goals are to elucidate the fundamental mechanisms of the host lncRNA-regulated anti-M.tb response in macrophages and investigate the potential application of host lncRNAs as novel host-directed therapies for tuberculosis. Our preliminary data indicate that M.tb infection induces the expression of host lncRNA, fetal-lethal noncoding development regulatory RNA (FENDRR), in mouse and human macrophages in vitro and in vivo. Additionally, FENDRR-knockdown facilitates M.tb growth in mouse and human macrophages in cell culture. Furthermore, FENDRR interacts with host iron-responsive element-binding protein 1(Irp1) and down-regulates host microRNA miR-214 in mouse macrophages post M.tb infection. We hypothesize that FENDRR mediates the anti-M.tb response by controlling intracellular iron availability via interfering with iron-responsive protein IRP1 and by upregulating the anti-M.tb protein enhancer of Zeste homolog 1 (EZH1) through competing with the host microRNA miR-214. We will test our hypothesis using mouse and human macrophage cell culture, and mouse models of tuberculosis. Aim I will investigate the mechanism by which M.tb induces FENDRR expression via the TLR2-Myd88-p38-C/EBPβ axis. Aim II will define the mechanisms by which FENDRR exerts anti-M.tb response. Aim III will evaluate the functional roles and mechanisms of action of FENDRR in mouse models of tuberculosis. The proposed studies will reveal a novel anti-M.tb pathway mediated by host lncRNA FENDRR.