title: Mycobacterium tuberculosis decreases human macrophage IFN-γ responsiveness through miR-132 and miR-26a.
abstract: IFN-γ-activated macrophages play an essential role in controlling intracellular pathogens; however, macrophages also serve as the cellular home for the intracellular pathogen Mycobacterium tuberculosis. Based on previous evidence that M. tuberculosis can modulate host microRNA (miRNA) expression, we examined the miRNA expression profile of M. tuberculosis-infected primary human macrophages. We identified 31 differentially expressed miRNAs in primary human macrophages during M. tuberculosis infection by NanoString and confirmed our findings by quantitative real-time RT-PCR. In addition, we determined a role for two miRNAs upregulated upon M. tuberculosis infection, miR-132 and miR-26a, as negative regulators of transcriptional coactivator p300, a component of the IFN-γ signaling cascade. Knockdown expression of miR-132 and miR-26a increased p300 protein levels and improved transcriptional, translational, and functional responses to IFN-γ in human macrophages. Collectively, these data validate p300 as a target of miR-132 and miR-26a, and demonstrate a mechanism by which M. tuberculosis can limit macrophage responses to IFN-γ by altering host miRNA expression.
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
authors.forename: Bin
authors.initials: B
authors.lastname: Ni
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
authors.forename: William P
authors.initials: WP
authors.lastname: Lafuse
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Landes
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210; Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210 larry.schlesinger@osumc.edu.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D035683:MicroRNAs; D012333:RNA, Messenger; D017452:Receptors, IgG; D050880:p300-CBP Transcription Factors; C547077:MIRN132 microRNA, human; C528163:MIRN26 microRNA, human