title: PAR-1 contributes to the innate immune response during viral infection.
abstract: Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1(-/-) mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1(+/+) mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1(-/-) mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1(+/+) mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.
authors: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: Silvio
authors: S
authors: Antoniak
authors: A Phillip
authors: AP
authors: Owens
authors: Martin
authors: M
authors: Baunacke
authors: Julie C
authors: JC
authors: Williams
authors: Rebecca D
authors: RD
authors: Lee
authors: Alice
authors: A
authors: Weithäuser
authors: Patricia A
authors: PA
authors: Sheridan
authors: Ronny
authors: R
authors: Malz
authors: James P
authors: JP
authors: Luyendyk
authors: Denise A
authors: DA
authors: Esserman
authors: JoAnn
authors: J
authors: Trejo
authors: Daniel
authors: D
authors: Kirchhofer
authors: Burns C
authors: BC
authors: Blaxall
authors: Rafal
authors: R
authors: Pawlinski
authors: Melinda A
authors: MA
authors: Beck
authors: Ursula
authors: U
authors: Rauch
authors: Nigel
authors: N
authors: Mackman
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000378:metabolism; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000378:metabolism; D004770:Enterovirus / Q000276:immunology / Q000502:physiology; D005337:Fibrin / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology / Q000502:physiology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000097:blood / Q000276:immunology / Q000821:virology; D009206:Myocardium / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D019210:Troponin I / Q000097:blood
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D044463:Receptor, PAR-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D019210:Troponin I; D016899:Interferon-beta; D005337:Fibrin; D013925:Thromboplastin; D013917:Thrombin
references: Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22
references: 15117736
references: Science. 2004 Aug 27;305(5688):1283-6
references: 15333838
references: Annu Rev Immunol. 2002;20:197-216
references: 11861602
references: Immunol Lett. 2009 Jan 29;122(1):1-11
references: 19059436
references: Circ Shock. 1991 Mar;33(3):127-34
references: 2044206
references: J Mol Cell Cardiol. 2012 May;52(5):1056-65
references: 22326437
references: J Immunol. 2008 Mar 15;180(6):4200-7
references: 18322232
references: Circulation. 2003 Jun 10;107(22):2793-8
references: 12771005
references: J Clin Invest. 1994 Jan;93(1):114-20
references: 8282778
references: Mucosal Immunol. 2010 Jan;3(1):29-39
references: 19865078
references: J Interferon Cytokine Res. 2005 Feb;25(2):103-12
references: 15695931
references: Blood. 2011 Sep 1;118(9):2589-98
references: 21613262
references: Am J Physiol Lung Cell Mol Physiol. 2004 Feb;286(2):L388-98
references: 14633513
references: PLoS One. 2009;4(1):e4127
references: 19122812
references: Trends Immunol. 2005 Jul;26(7):396-401
references: 15922665
references: PLoS One. 2011;6(6):e21484
references: 21760880
references: J Virol. 2005 Mar;79(5):2979-87
references: 15709018
references: Cell Immunol. 1996 Aug 25;172(1):35-42
references: 8806804
references: J Biol Chem. 2009 May 22;284(21):14136-46
references: 19307177
references: Cell Immunol. 2011;267(1):9-16
references: 21092943
references: J Signal Transduct. 2011;2011:415195
references: 22175012
references: Circulation. 2008 Mar 25;117(12):1574-82
references: 18332263
references: Blood. 2012 Apr 12;119(15):3638-45
references: 22374699
references: J Clin Invest. 2013 Jan;123(1):206-14
references: 23202729
references: Circ Res. 2009 Mar 13;104(5):628-38
references: 19168435
references: Curr Opin Immunol. 1995 Feb;7(1):4-10
references: 7772280
references: Trends Immunol. 2004 Sep;25(9):461-4
references: 15324737
references: J Thromb Haemost. 2007 Jul;5 Suppl 1:24-31
references: 17635705
references: Biofactors. 2009 Jan-Feb;35(1):14-20
references: 19319841
references: J Virol. 2008 Aug;82(16):8149-60
references: 18550677
references: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20446-51
references: 19074283
references: J Thromb Haemost. 2009 May;7(5):871-8
references: 19228282
references: Cytokine. 2012 Mar;57(3):337-46
references: 22200507
references: Thromb Haemost. 1983 Feb 28;49(1):5-7
references: 6845273
references: J Biol Chem. 2010 Jul 23;285(30):23208-23
references: 20472559
references: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1687-93
references: 17556654
references: J Clin Invest. 2012 Feb;122(2):558-68
references: 22214850
references: Mol Cell Biol. 1989 Jun;9(6):2752-5
references: 2503712
references: J Thromb Thrombolysis. 2010 Aug;30(2):164-71
references: 20155436
references: Circulation. 2001 Feb 6;103(5):756-61
references: 11156890
references: Cell Immunol. 2012;274(1-2):121-9
references: 22341560
references: J Biol Chem. 1990 Jun 15;265(17):9782-7
references: 1693617
references: J Nutr. 2007 May;137(5):1236-43
references: 17449587
references: Blood. 2004 Dec 15;104(13):4157-64
references: 15315972
references: Front Biosci. 1998 Sep 01;3:D973-84
references: 9727083
references: Br J Pharmacol. 2010 May;160(2):191-203
references: 20423334
references: J Immunol. 2011 Feb 15;186(4):2561-70
references: 21239721
references: Am J Pathol. 2006 May;168(5):1542-52
references: 16651621
references: J Immunol. 1987 Aug 1;139(3):913-8
references: 3036947
references: J Thromb Haemost. 2007 May;5(5):1055-61
references: 17461934
references: Circulation. 2007 Nov 13;116(20):2298-306
references: 17967980
references: Circ Res. 2002 Sep 20;91(6):532-9
references: 12242272
references: Immunol Rev. 2009 Jan;227(1):44-53
references: 19120474
references: Mucosal Immunol. 2008 Mar;1(2):156-68
references: 19079173
references: Blood. 2009 Jan 15;113(3):714-22
references: 18971420
references: Circulation. 2004 Dec 7;110(23):3540-3
references: 15249500
references: Circulation. 2012 Jun 19;125(24):2993-3003
references: 22610965
references: J Biol Chem. 2008 Sep 5;283(36):24314-25
references: 18622013
references: Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H69-76
references: 17434974
references: Blood. 2010 Jan 14;115(2):161-7
references: 19828697
references: Thromb Haemost. 1996 Dec;76(6):860-6
references: 8972001
references: Thromb Haemost. 2008 May;99(5):936-43
references: 18449425
references: J Thromb Haemost. 2011 Jul;9 Suppl 1:182-8
references: 21781254
references: IUBMB Life. 2011 Jun;63(6):383-9
references: 21438116
references: Blood. 2005 Jan 1;105(1):178-85
references: 15367435
references: N Engl J Med. 2012 Jan 5;366(1):20-33
references: 22077816
references: Basic Res Cardiol. 2007 Jul;102(4):350-8
references: 17468933
references: Trends Cardiovasc Med. 2009 Jan;19(1):21-6
references: 19467450
references: Physiology (Bethesda). 2006 Aug;21:281-8
references: 16868317
references: Innate Immun. 2012 Apr;18(2):193-203
references: 21239455
references: Nature. 2000 Sep 14;407(6801):258-64
references: 11001069
references: Proc Natl Acad Sci U S A. 1990 Sep;87(18):7095-9
references: 2169619
references: J Immunol. 2009 Jun 15;182(12):7795-802
references: 19494303
references: Circ Res. 2000 May 26;86(10):1054-61
references: 10827135
references: Mol Cell Biol. 1991 Sep;11(9):4732-8
references: 1875949
references: J Exp Med. 2008 Aug 4;205(8):1739-46
references: 18606855
references: Clin Dev Immunol. 2012;2012:129486
references: 22013485
references: Trends Immunol. 2007 Dec;28(12):541-50
references: 17977790
references: N Engl J Med. 2012 Apr 12;366(15):1404-13
references: 22443427
references: Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2136-42
references: 20724699
references: Mol Pharmacol. 2005 Jan;67(1):2-11
references: 15371558
references: Prog Cardiovasc Dis. 2010 Jan-Feb;52(4):274-88
references: 20109598
references: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H251-8
references: 16936008
references: J Infect Dis. 2003 Dec 1;188(11):1618-29
references: 14639531
references: N Engl J Med. 2009 Sep 17;361(12):1139-51
references: 19717844
references: J Immunol. 2007 Mar 15;178(6):3368-72
references: 17339430
references: Crit Care. 2010;14(2):R65
references: 20398279
references: J Leukoc Biol. 2008 Jun;83(6):1309-22
references: 18347074
references: Proc Natl Acad Sci U S A. 1985 Jul;82(14):4818-22
references: 2410905
references: J Thromb Haemost. 2005 May;3(5):1098-9
references: 15869619
references: Am J Pathol. 1993 May;142(5):1458-70
references: 7684196
references: J Mol Cell Cardiol. 2008 Jul;45(1):118-26
references: 18495150
references: Thromb Haemost. 2001 Jul;86(1):298-307
references: 11487018