title: A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection.
abstract: The interferon (IFN)-induced transmembrane (IFITM) proteins are critical mediators of the host antiviral response. Here, we expand the role of IFITM proteins to host defense against intracellular bacterial infection by demonstrating that they restrict Mycobacterium tuberculosis (MTb) intracellular growth. Simultaneous knockdown of IFITM1, IFITM2, and IFITM3 by RNAi significantly enhances MTb growth in human monocytic and alveolar/epithelial cells, whereas individual overexpression of each IFITM impairs MTb growth in these cell types. Furthermore, MTb infection, Toll-like receptor 2 and 4 ligands, and several proinflammatory cytokines induce IFITM1-3 gene expression in human myeloid cells. We find that IFITM3 co-localizes with early and, in particular, late MTb phagosomes, and overexpression of IFITM3 enhances endosomal acidification in MTb-infected monocytic cells. These findings provide evidence that the antiviral IFITMs participate in the restriction of mycobacterial growth, and they implicate IFITM-mediated endosomal maturation in its antimycobacterial activity.
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA. Electronic address: shahin.ranjbar@childrens.harvard.edu.
authors.forename: Shahin
authors.initials: S
authors.lastname: Ranjbar
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Viraga
authors.initials: V
authors.lastname: Haridas
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Jasenosky
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: James V
authors.initials: JV
authors.lastname: Falvo
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA. Electronic address: anne.goldfeld@childrens.harvard.edu.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Goldfeld
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D010587:Phagocytosis; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; C080081:IFITM2 protein, human; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C062010:leu-13 antigen