title: Evidence for postinitiation regulation of mRNA biogenesis in tuberculosis.
abstract: Mycobacterium tuberculosis infection alters macrophage gene expression and macrophage response to IFN-γ, a critical host defense cytokine. However, regulation of these changes is poorly understood. We report discordance of changes in nascent transcript and total nuclear RNA abundance for the transcription factors STAT1 and IRF1, together with lack of effect on their RNA half-lives, in human THP-1 cells infected with M. tuberculosis and stimulated with IFN-γ. The results indicate that negative postinitiation regulation of mRNA biogenesis limits the expression of these factors, which mediate host defense against M. tuberculosis through the cellular response to IFN-γ. Consistent with the results for STAT1 and IRF1, transcriptome analysis reveals downregulation of postinitiation mRNA biogenesis processes and pathways by infection, with and without IFN-γ stimulation. Clinical relevance for regulation of postinitiation mRNA biogenesis is demonstrated by studies of donor samples showing that postinitiation mRNA biogenesis pathways are repressed in latent tuberculosis infection compared with cured disease and in active tuberculosis compared with ongoing treatment or with latent tuberculosis. For active disease and latent infection donors from two populations (London, U.K., and The Gambia), each analyzed using a different platform, pathway-related gene expression differences were highly correlated, demonstrating substantial specificity in the effect. Collectively, the molecular and bioinformatic analyses point toward downregulation of postinitiation mRNA biogenesis pathways as a means by which M. tuberculosis infection limits expression of immunologically essential transcription factors. Thus, negative regulation of postinitiation mRNA biogenesis can constrain the macrophage response to infection and overall host defense against tuberculosis.
authors: Knowledge Synthesis, Inc., Berkeley, CA 94716, USA.
authors: Hugh
authors: H
authors: Salamon
authors: Yaming
authors: Y
authors: Qiao
authors: Jeff C
authors: JC
authors: Cheng
authors: Ken D
authors: KD
authors: Yamaguchi
authors: Patricia
authors: P
authors: Soteropoulos
authors: Michael
authors: M
authors: Weiden
authors: Maria Laura
authors: ML
authors: Gennaro
authors: Richard
authors: R
authors: Pine
mesh_terms: D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000502:physiology; D055985:Latent Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma
references: J Biol Chem. 2001 Sep 21;276(38):35482-93
references: 11461902
references: Nat Rev Genet. 2011 Nov 03;12(12):833-45
references: 22048664
references: Nature. 2010 Aug 19;466(7309):973-7
references: 20725040
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D691-7
references: 21067998
references: Nucleic Acids Res. 1988 Feb 25;16(4):1371-8
references: 3126485
references: J Immunol. 2004 Mar 1;172(5):2935-43
references: 14978096
references: Bioinformatics. 2001 Jun;17(6):509-19
references: 11395427
references: Mol Cell Biol. 1990 Jun;10(6):2448-57
references: 2342456
references: Nat Genet. 2003 Mar;33(3):388-91
references: 12590259
references: Nat Rev Immunol. 2012 Jul 13;12(8):581-91
references: 22790178
references: Infect Immun. 2003 Aug;71(8):4487-97
references: 12874328
references: J Leukoc Biol. 2009 Nov;86(5):1247-58
references: 19652026
references: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D428-32
references: 15608231
references: Cell. 1996 Feb 9;84(3):443-50
references: 8608598
references: Blood. 2000 Jun 1;95(11):3548-54
references: 10828042
references: Clin Immunol. 2004 Jan;110(1):2-12
references: 14986673
references: PLoS One. 2011;6(10):e26938
references: 22046420
references: Clin Infect Dis. 2007 Nov 15;45(10):1290-5
references: 17968823
references: PLoS Pathog. 2008 Dec;4(12):e1000229
references: 19057661
references: Pharmacogenomics J. 2013 Oct;13(5):443-51
references: 22711062
references: Microbiol Immunol. 2002;46(11):751-60
references: 12516771
references: Tohoku J Exp Med. 2004 Jan;202(1):41-50
references: 14738323
references: Nat Rev Genet. 2010 Jun;11(6):426-37
references: 20421872
references: J Exp Med. 1994 Sep 1;180(3):977-84
references: 7520478
references: J Biol Chem. 2002 Jun 21;277(25):22377-85
references: 11948194
references: Gene. 2008 Nov 1;423(2):97-107
references: 18718859
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Mol Immunol. 2007 Jan;44(4):284-94
references: 16675018
references: J Neuroimmunol. 2008 Mar;195(1-2):116-20
references: 18279974
references: Eur Respir J. 2009 Apr;33(4):871-81
references: 19251779
references: Microbes Infect. 2007 Sep;9(11):1359-67
references: 17890129
references: Infect Immun. 2003 Jan;71(1):254-9
references: 12496173
references: Cell. 2002 Jul 26;110(2):191-202
references: 12150927
references: ACS Chem Biol. 2008 Oct 17;3(10):609-17
references: 18817380
references: Cell. 1996 Feb 9;84(3):431-42
references: 8608597
references: J Immunol. 1999 Oct 1;163(7):3898-906
references: 10490990
references: Genes Dev. 2004 Oct 15;18(20):2437-68
references: 15489290
references: PLoS One. 2009 Jul 24;4(7):e6329
references: 19629181
references: EMBO J. 1988 Jan;7(1):57-67
references: 3359995
references: J Exp Med. 2003 Oct 6;198(7):987-97
references: 14517275
references: Science. 1994 Mar 18;263(5153):1612-5
references: 7510419
references: J Exp Med. 2010 Mar 15;207(3):591-605
references: 20212068
references: J Biol Chem. 2004 Jun 25;279(26):27699-708
references: 15082713
references: Infect Immun. 2003 May;71(5):2487-97
references: 12704120
references: J Infect Dis. 1997 Aug;176(2):478-84
references: 9237715
references: Nat Rev Mol Cell Biol. 2004 Sep;5(9):727-38
references: 15340380
references: J Biol Chem. 2005 Dec 2;280(48):39950-61
references: 16207706
references: Genome Biol. 2005;6(2):R16
references: 15693945
references: J Immunol. 2000 Aug 15;165(4):2028-39
references: 10925286
references: J Immunol. 2003 Aug 15;171(4):2042-9
references: 12902509
references: Arch Intern Med. 2003 May 12;163(9):1009-21
references: 12742798
references: J Biol Chem. 2009 May 8;284(19):12792-800
references: 19282286
references: Curr Biol. 2002 Mar 19;12(6):467-71
references: 11909531
references: J Exp Med. 2001 Oct 15;194(8):1123-40
references: 11602641
references: J Immunol. 2006 Apr 15;176(8):5078-83
references: 16585605
references: J Immunol. 2005 May 1;174(9):5687-94
references: 15843570
references: Blood. 2001 Jul 15;98(2):436-41
references: 11435314
references: J Immunol. 2003 Dec 15;171(12):6766-73
references: 14662881
references: Wiley Interdiscip Rev RNA. 2011 Mar-Apr;2(2):277-98
references: 21957010
references: EMBO J. 1994 Jan 1;13(1):158-67
references: 8306959
references: Infect Immun. 2004 Nov;72(11):6603-14
references: 15501793