title: The Lyme disease spirochete Borrelia burgdorferi utilizes multiple ligands, including RNA, for interferon regulatory factor 3-dependent induction of type I interferon-responsive genes.
abstract: We recently discovered a critical role for type I interferon (IFN) in the development of murine Lyme arthritis. Borrelia burgdorferi-mediated induction of IFN-responsive genes by bone marrow-derived macrophages (BMDMs) was dependent upon a functional type I IFN receptor but independent of Toll-like receptor 2 (TLR2), TLR4, TLR9, and the adapter molecule MyD88. We now demonstrate that induction of the IFN transcriptional profile in B. burgdorferi-stimulated BMDMs occurs independently of the adapter TRIF and of the cytoplasmic sensor NOD2. In contrast, B. burgdorferi-induced transcription of these genes was dependent upon a rapid STAT1 feedback amplification pathway. IFN profile gene transcription was IRF3 dependent but did not utilize B. burgdorferi-derived DNA or DNase-sensitive ligands. Instead, IFN-responsive gene expression could be induced by B. burgdorferi-derived RNA. Interferon regulatory factor 3 (IRF3)-dependent IFN profile gene transcription was also induced by sonicated bacteria, by the lipoprotein OspA, and by factors released into the BSKII medium during culture of B. burgdorferi. The IFN-stimulatory activity of B. burgdorferi culture supernatants was not destroyed by nuclease treatment. Nuclease digestion also had no effect on IFN profile induction mediated by sonicated B. burgdorferi. Thus, B. burgdorferi-derived RNA, OspA, and non-nucleic acid ligands present in both sonicated bacteria and B. burgdorferi culture medium contribute to type I IFN-responsive gene induction. These findings suggest that B. burgdorferi invasion of joint tissue and the resultant type I IFN induction associated with Lyme arthritis development may involve multiple triggering ligands.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Miller
authors.forename: Heather
authors.initials: H
authors.lastname: Maylor-Hagen
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: John H
authors.initials: JH
authors.lastname: Weis
authors.forename: Janis J
authors.initials: JJ
authors.lastname: Weis
mesh_terms: D000818:Animals; D025065:Borrelia burgdorferi / Q000235:genetics / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D005798:Genes, Bacterial / Q000235:genetics / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000502:physiology; D008193:Lyme Disease / Q000382:microbiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse
references.citation: J Exp Med. 2003 Mar 17;197(6):777-88
references.pmid: 12642605
references.citation: J Exp Med. 2007 May 14;204(5):987-94
references.pmid: 17452523
references.citation: Infect Immun. 2004 Jun;72(6):3195-203
references.pmid: 15155621
references.citation: J Immunol. 2007 Feb 15;178(4):2517-26
references.pmid: 17277160
references.citation: Vector Borne Zoonotic Dis. 2006 Spring;6(1):103-12
references.pmid: 16584333
references.citation: J Immunol. 2003 Sep 1;171(5):2660-70
references.pmid: 12928420
references.citation: Infect Immun. 1983 Aug;41(2):795-804
references.pmid: 6192088
references.citation: J Immunol. 2007 Mar 1;178(5):3153-60
references.pmid: 17312163
references.citation: Infect Immun. 2008 Mar;76(3):1153-62
references.pmid: 18086805
references.citation: J Immunol. 1999 May 15;162(10):5666-70
references.pmid: 10229796
references.citation: Infect Immun. 2009 Aug;77(8):3320-7
references.pmid: 19487481
references.citation: Infect Immun. 1994 Oct;62(10):4632-6
references.pmid: 7927731
references.citation: J Immunol. 2008 Dec 15;181(12):8492-503
references.pmid: 19050267
references.citation: J Immunol. 1999 Sep 1;163(5):2382-6
references.pmid: 10452971
references.citation: J Immunol. 2000 Jul 15;165(2):618-22
references.pmid: 10878331
references.citation: Scand J Rheumatol. 2005 Nov-Dec;34(6):485-8
references.pmid: 16393774
references.citation: Rheumatology (Oxford). 2007 Apr;46(4):657-65
references.pmid: 17085467
references.citation: Immunity. 2006 Jan;24(1):93-103
references.pmid: 16413926
references.citation: Biotechniques. 1998 Jun;24(6):954-8, 960, 962
references.pmid: 9631186
references.citation: J Interferon Cytokine Res. 2006 Jun;26(6):390-9
references.pmid: 16734559
references.citation: J Immunol. 2007 Mar 1;178(5):3170-6
references.pmid: 17312165
references.citation: J Immunol. 2005 Mar 1;174(5):2499-506
references.pmid: 15728455
references.citation: PLoS Pathog. 2009 May;5(5):e1000444
references.pmid: 19461888
references.citation: J Biol Chem. 2002 Jan 4;277(1):639-44
references.pmid: 11668183
references.citation: Cell Host Microbe. 2008 Dec 11;4(6):543-54
references.pmid: 19064255
references.citation: Infect Immun. 2009 Mar;77(3):1238-45
references.pmid: 19139200
references.citation: Biochem J. 2009 Apr 28;420(1):1-16
references.pmid: 19382893
references.citation: Semin Arthritis Rheum. 2002 Dec;32(3):163-73
references.pmid: 12528081
references.citation: J Immunol. 2009 Oct 15;183(8):5279-92
references.pmid: 19794067
references.citation: J Biol Chem. 2008 Jul 18;283(29):19879-87
references.pmid: 18480050
references.citation: Infect Immun. 1992 Feb;60(2):455-64
references.pmid: 1730476
references.citation: Cell Microbiol. 2006 Jun;8(6):907-22
references.pmid: 16681834
references.citation: PLoS Pathog. 2007 Mar;3(3):e51
references.pmid: 17397264
references.citation: Infect Immun. 1994 Sep;62(9):3663-71
references.pmid: 7520417
references.citation: PLoS Pathog. 2008 Jan;4(1):e6
references.pmid: 18193943
references.citation: Mol Microbiol. 2003 Jun;48(6):1665-77
references.pmid: 12791146
references.citation: PLoS Pathog. 2009 Jul;5(7):e1000500
references.pmid: 19578435
references.citation: Infect Immun. 2006 Mar;74(3):1462-70
references.pmid: 16495516
references.citation: Infect Immun. 1999 Oct;67(10):5142-50
references.pmid: 10496888
references.citation: J Immunol. 2006 Nov 15;177(10):7059-66
references.pmid: 17082622
references.citation: J Immunol. 2004 Aug 1;173(3):2003-10
references.pmid: 15265935
references.citation: Infect Immun. 2009 Aug;77(8):3302-11
references.pmid: 19487472
references.citation: Immunity. 1998 Jul;9(1):143-50
references.pmid: 9697844
references.citation: Immunity. 2000 Oct;13(4):539-48
references.pmid: 11070172
references.citation: FEMS Immunol Med Microbiol. 2008 Jan;52(1):124-33
references.pmid: 18081848
references.citation: Yale J Biol Med. 1984 Jul-Aug;57(4):521-5
references.pmid: 6393604
references.citation: PLoS Pathog. 2009 Nov;5(11):e1000665
references.pmid: 19936053
references.citation: Infect Immun. 1987 Sep;55(9):2311-3
references.pmid: 3623705
references.citation: Science. 1998 Dec 11;282(5396):2085-8
references.pmid: 9851930
references.citation: J Immunol. 2008 Jun 15;180(12):8306-15
references.pmid: 18523297
references.citation: Eur J Immunol. 1976 Mar;6(3):213-7
references.pmid: 1086777
references.citation: Am J Pathol. 1991 Aug;139(2):263-73
references.pmid: 1867318