title: Enteropathogenic Escherichia coli inhibits type I interferon- and RNase L-mediated host defense to disrupt intestinal epithelial cell barrier function.
abstract: Enteropathogenic Escherichia coli (EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.
authors.affiliation: Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tiha M
authors.initials: TM
authors.lastname: Long
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shahista
authors.initials: S
authors.lastname: Nisa
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Donnenberg
authors.affiliation: Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA bhassel@som.umaryland.edu.
authors.forename: Bret A
authors.initials: BA
authors.lastname: Hassel
mesh_terms: D018938:Caco-2 Cells; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D054308:Enteropathogenic Escherichia coli / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000502:physiology*
chemical_list: D029968:Escherichia coli Proteins; C506689:Z0990 protein, E coli; D016899:Interferon-beta; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease
references.citation: Nat Rev Immunol. 2010 Oct;10(10):735-44
references.pmid: 20865020
references.citation: Immunity. 2012 Jul 27;37(1):171-86
references.pmid: 22749822
references.citation: Ann N Y Acad Sci. 2012 Jul;1258:9-18
references.pmid: 22731710
references.citation: Science. 2010 Jan 15;327(5963):286-90
references.pmid: 20075243
references.citation: Dig Dis. 2009;27(4):450-4
references.pmid: 19897959
references.citation: Ann N Y Acad Sci. 2012 Jul;1258:43-51
references.pmid: 22731714
references.citation: J Virol. 2012 Oct;86(20):11311-21
references.pmid: 22875977
references.citation: J Interferon Cytokine Res. 2014 Apr;34(4):275-88
references.pmid: 24697205
references.citation: J Interferon Cytokine Res. 2011 Jan;31(1):49-57
references.pmid: 21190483
references.citation: Mol Immunol. 2009 Dec;47(2-3):560-6
references.pmid: 19853919
references.citation: J Biol Chem. 2012 Dec 21;287(52):43651-64
references.pmid: 23109342
references.citation: Infect Immun. 1993 Jul;61(7):2755-62
references.pmid: 8514377
references.citation: J Biol Chem. 2008 Dec 12;283(50):35212-22
references.pmid: 18809683
references.citation: Am J Pathol. 2005 Feb;166(2):409-19
references.pmid: 15681825
references.citation: Inflamm Bowel Dis. 2013 May;19(6):1295-305
references.pmid: 23567782
references.citation: Mol Cell Biol. 2006 Mar;26(6):2408-18
references.pmid: 16508015
references.citation: Gut. 1985 Jun;26(6):556-61
references.pmid: 2408970
references.citation: Nature. 2001 May 31;411(6837):603-6
references.pmid: 11385577
references.citation: Cell Host Microbe. 2013 Jan 16;13(1):87-99
references.pmid: 23332158
references.citation: J Bacteriol. 2013 Oct;195(19):4476-83
references.pmid: 23913321
references.citation: Immunity. 2011 Feb 25;34(2):213-23
references.pmid: 21349431
references.citation: Mol Microbiol. 2011 Jun;80(6):1420-38
references.pmid: 21488979
references.citation: Nature. 2013 Sep 12;501(7466):247-51
references.pmid: 24025841
references.citation: PLoS Pathog. 2010 Dec 16;6(12):e1001231
references.pmid: 21187904
references.citation: Cell Microbiol. 2007 Aug;9(8):1909-21
references.pmid: 17388785
references.citation: Microbes Infect. 2013 Feb;15(2):147-51
references.pmid: 23142035
references.citation: J Immunol. 2010 Oct 1;185(7):4118-27
references.pmid: 20833837
references.citation: Mol Cell Biol. 2006 Mar;26(6):2399-407
references.pmid: 16508014
references.citation: Cell Res. 2007 Oct;17(10):858-68
references.pmid: 17893708
references.citation: Nat Rev Immunol. 2012 Jan 06;12(2):125-35
references.pmid: 22222875
references.citation: PLoS One. 2013 Dec 04;8(12):e81269
references.pmid: 24324683
references.citation: RNA. 2008 Jun;14(6):1026-36
references.pmid: 18426919
references.citation: Mucosal Immunol. 2008 Nov;1 Suppl 1:S5-9
references.pmid: 19079230
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20816-21
references.pmid: 19075243
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D1040-6
references.pmid: 23203888
references.citation: Mol Biol Cell. 2011 Jul 15;22(14):2436-47
references.pmid: 21613538
references.citation: Eur J Gastroenterol Hepatol. 1995 Jul;7(7):597-602
references.pmid: 8590152
references.citation: J Clin Invest. 2008 May;118(5):1680-90
references.pmid: 18382764
references.citation: Infect Immun. 2007 Feb;75(2):565-73
references.pmid: 17118974
references.citation: Inflammation. 2012 Feb;35(1):23-32
references.pmid: 21170673
references.citation: Front Biosci (Schol Ed). 2012 Jan 01;4:767-86
references.pmid: 22202089
references.citation: J Virol. 1983 Jun;46(3):1051-5
references.pmid: 6190010
references.citation: J Cell Sci. 2004 Mar 1;117(Pt 7):1247-57
references.pmid: 14996944
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17390-5
references.pmid: 21960441
references.citation: Nature. 2007 Jul 26;448(7152):427-34
references.pmid: 17653185
references.citation: Cytokine Growth Factor Rev. 2007 Oct-Dec;18(5-6):381-8
references.pmid: 17681844
references.citation: Scand J Immunol. 2011 Apr;73(4):268-83
references.pmid: 21204905
references.citation: Infect Immun. 2011 Sep;79(9):3552-62
references.pmid: 21746856
references.citation: Gastroenterology. 2002 Jul;123(1):163-72
references.pmid: 12105845
references.citation: Biochim Biophys Acta. 2008 Mar;1778(3):588-600
references.pmid: 17916321
references.citation: Hepatology. 2013 Feb;57(2):461-9
references.pmid: 22996292
references.citation: Inflamm Bowel Dis. 2012 May;18(5):955-67
references.pmid: 21953855
references.citation: EMBO Rep. 2012 Aug;13(8):684-98
references.pmid: 22801555
references.citation: RNA Biol. 2009 Jul-Aug;6(3):305-15
references.pmid: 19411840
references.citation: Immunity. 2012 Jul 27;37(1):10-2
references.pmid: 22840839
references.citation: J Immunol. 2013 Sep 1;191(5):2771-9
references.pmid: 23913971
references.citation: Lancet. 2013 Jul 20;382(9888):209-22
references.pmid: 23680352
references.citation: Wiley Interdiscip Rev RNA. 2011 Jan-Feb;2(1):58-78
references.pmid: 21956969
references.citation: J Biol Chem. 2004 Jan 9;279(2):1123-31
references.pmid: 14570908
references.citation: Eur J Gastroenterol Hepatol. 1995 Jul;7(7):593-4
references.pmid: 8590150
references.citation: Biochim Biophys Acta. 2013 Jun-Jul;1829(6-7):666-79
references.pmid: 23428348
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
references.pmid: 10829079
references.citation: Immunity. 2012 Jul 27;37(1):158-70
references.pmid: 22705104
references.citation: Inflamm Bowel Dis. 2012 Sep;18(9):1735-42
references.pmid: 22275310
references.citation: Ann N Y Acad Sci. 2009 May;1165:169-74
references.pmid: 19538303
references.citation: FEBS J. 2010 Nov;277(21):4464-73
references.pmid: 20875083
references.citation: Microb Pathog. 2010 Jan;48(1):28-34
references.pmid: 19833191
references.citation: Cell Microbiol. 2006 Apr;8(4):634-45
references.pmid: 16548889
references.citation: J Virol. 2007 Dec;81(23):12720-9
references.pmid: 17804500
references.citation: Nat Rev Immunol. 2012 Apr 25;12(5):367-82
references.pmid: 22531325
references.citation: Infect Immun. 2000 Jun;68(6):3689-95
references.pmid: 10816529
references.citation: Oncogene. 2013 Oct 10;32(41):4960-9
references.pmid: 23503457
references.citation: Cell Microbiol. 2003 Jun;5(6):359-72
references.pmid: 12780774
references.citation: Nucleic Acids Res. 2012 Sep;40(16):7739-52
references.pmid: 22718976
references.citation: J Biol Chem. 2004 Jul 30;279(31):32393-400
references.pmid: 15187092
references.citation: Cell Microbiol. 2000 Aug;2(4):305-15
references.pmid: 11207587
references.citation: Mol Cell Biol. 1999 Jun;19(6):4311-23
references.pmid: 10330172
references.citation: Nat Immunol. 2013 Jul;14(7):660-7
references.pmid: 23778793
references.citation: Ann N Y Acad Sci. 2012 Jul;1258:149-58
references.pmid: 22731728
references.citation: PLoS Pathog. 2013;9(11):e1003727
references.pmid: 24244159
references.citation: RNA. 2010 Nov;16(11):2108-19
references.pmid: 20833746
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000743
references.pmid: 20126447
references.citation: J Virol. 1998 Apr;72(4):2752-9
references.pmid: 9525594
references.citation: Gastroenterology. 2006 Oct;131(4):1153-63
references.pmid: 17030185
references.citation: Blood. 2006 Jun 15;107(12):4790-7
references.pmid: 16514065
references.citation: Ann Neurol. 2004 Aug;56(2):192-205
references.pmid: 15293271
references.citation: Nat Cell Biol. 1999 Jun;1(2):94-7
references.pmid: 10559880
references.citation: EMBO J. 1997 Nov 3;16(21):6355-63
references.pmid: 9351818
references.citation: Immunobiology. 2007;212(9-10):895-901
references.pmid: 18086388
references.citation: J Clin Invest. 2001 Mar;107(5):621-9
references.pmid: 11238563
references.citation: Trends Immunol. 2006 Jan;27(1):40-8
references.pmid: 16356769
references.citation: Nat Rev Drug Discov. 2010 Apr;9(4):293-307
references.pmid: 20380038
references.citation: Cell Microbiol. 2010 Jul;12(7):881-90
references.pmid: 20482555
references.citation: PLoS Pathog. 2010 May 13;6(5):e1000898
references.pmid: 20485572
references.citation: Nature. 2007 Aug 16;448(7155):816-9
references.pmid: 17653195
references.citation: Cell Res. 2007 Dec;17(12):974-5
references.pmid: 18075517
references.citation: J Biol Chem. 2012 May 11;287(20):16955-64
references.pmid: 22461621
references.citation: FEBS J. 2008 Dec;275(23):6022-32
references.pmid: 19016848
references.citation: Endothelium. 2003;10(6):299-307
references.pmid: 14741845
references.citation: EMBO J. 2011 Jan 5;30(1):221-31
references.pmid: 21113130
references.citation: Gut Microbes. 2012 May-Jun;3(3):267-71
references.pmid: 22572833
references.citation: Cell. 1993 Mar 12;72(5):753-65
references.pmid: 7680958
references.citation: Mol Cell Biol Res Commun. 2000 Aug;4(2):122-8
references.pmid: 11170843
references.citation: Infect Immun. 2006 May;74(5):2522-36
references.pmid: 16622187