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.