The role of FENDRR in host defense against Mycobacterium tuberculosis infection

项目摘要 结核分枝杆菌（Mycobacterium tuberculosis，M.tb）是一种引起人类结核病的细胞内细菌病原体。 结核病仍然是一个重大的全球公共卫生威胁。每年大约有1000万活跃的 结核病病例和140万例死亡。宿主-结核分枝杆菌相互作用的机制仍有待进一步研究。 定义了长链非编码RNA（longnoncodingRNA，lncRNA）是一种长度超过200个核苷酸的非编码转录物。响应 对于细菌感染，哺乳动物细胞产生丰富的lncRNA来介导宿主-病原体相互作用， 这对宿主防御有利或有害。关于这方面的研究报告非常有限。 宿主lncRNA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 在宿主细胞中参与抵抗微生物感染的宿主防御。我们的长期目标是阐明 宿主lncRNA调节巨噬细胞抗结核反应的基本机制，并研究 宿主lncRNA作为结核病的新型宿主导向疗法的潜在应用。我们的初步数据 表明结核分枝杆菌感染诱导宿主lncRNA的表达，这是胎儿致死非编码发育调节因子 RNA（FENDRR），在小鼠和人巨噬细胞中的体外和体内。此外，FENDRR敲除 促进结核分枝杆菌在细胞培养物中的小鼠和人巨噬细胞中的生长。此外，FENDRR与 宿主铁反应元件结合蛋白1（Irp 1）下调小鼠中宿主microRNA miR-214 结核分枝杆菌感染后的巨噬细胞。我们假设FENDRR通过控制抗结核分枝杆菌抗体， 通过干扰铁反应蛋白IRP 1和上调抗结核分枝杆菌抗体， Zeste同源物1（EZH 1）的蛋白增强子通过与宿主microRNA miR-214竞争。我们将测试 我们的假设使用小鼠和人类巨噬细胞培养，以及小鼠结核病模型。我会瞄准的 研究结核分枝杆菌通过TLR 2-Myd 88-p38-C/EBPβ轴诱导FENDRR表达的机制。 目的II将定义FENDRR发挥抗结核分枝杆菌反应的机制。目标三将评估 FENDRR在结核病小鼠模型中的功能作用和作用机制。拟议的研究 将揭示由宿主lncRNA FENDRR介导的新型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.