title: The antiviral activity of poly-γ-glutamic acid, a polypeptide secreted by Bacillus sp., through induction of CD14-dependent type I interferon responses.
abstract: Poly-γ-glutamic acid (γ-PGA) is an anionic polypeptide secreted by Bacillus sp. that has been shown to activate immune cells through interactions with toll-like receptor 4 (TLR4). However, its ability to induce the type I interferon (IFN) response has not yet been characterized. Here, we demonstrate that γ-PGA induces type I IFN signaling pathway via the TLR4 signaling pathway. The induction required both myeloid differentiation factor 2 (MD2) and the pattern-recognition receptor CD14, which are two TLR4-associated accessory proteins. The γ-PGA with high molecular weights (2000 and 5000 kDa) was able to activate the subsequent signals through TLR4/MD2 to result in dimerization of IRF-3, a transcription factor required for IFN gene expression, leading to increases in mRNA levels of the type I IFN-response genes, 2'-5' OAS and ISG56. Moreover, γ-PGA (2000 kDa) displayed an antiviral activity against SARS coronavirus and hepatitis C virus. Our results identify high-molecular weight γ-PGA as a TLR4 ligand and demonstrate that γ-PGA requires both CD14 and MD2 for the activation of type I IFN responses. Our results suggest that the microbial biopolymer γ-PGA may have therapeutic potential against a broad range of viruses sensitive to type I IFNs.
authors.affiliation: Department of Biotechnology and Center for Protein Function Control, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Lee
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Dae-Gyun
authors.initials: DG
authors.lastname: Ahn
authors.forename: Hee
authors.initials: H
authors.lastname: Cho
authors.forename: Moon-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Han
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Oh
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000627:therapeutic use*; D001407:Bacillus / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D051379:Mice; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D018950:Lipopolysaccharide Receptors; D051197:Toll-Like Receptor 4; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid
keywords: Antiviral agent; Hepatitis C virus; Interferon; Poly-γ-glutamic acid; SARS coronavirus; TLR4
references.citation: J Biol Chem. 1998 Apr 10;273(15):8680-90
references.pmid: 9535844
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4186-91
references.pmid: 15010525
references.citation: Antiviral Res. 2011 Nov;92(2):346-55
references.pmid: 21945041
references.citation: Science. 1990 Sep 21;249(4975):1431-3
references.pmid: 1698311
references.citation: J Immunol. 2000 Jan 15;164(2):558-61
references.pmid: 10623794
references.citation: Genes Cells. 2001 Apr;6(4):375-88
references.pmid: 11318879
references.citation: Drugs. 2010;70(2):147-65
references.pmid: 20108989
references.citation: J Biol Chem. 1995 Apr 28;270(17):9904-10
references.pmid: 7537270
references.citation: J Immunol. 2001 Jan 1;166(1):15-9
references.pmid: 11123271
references.citation: Nat Med. 2007 May;13(5):543-51
references.pmid: 17479100
references.citation: J Exp Med. 2010 Nov 22;207(12):2689-701
references.pmid: 21078886
references.citation: Biomaterials. 2012 Oct;33(29):7182-93
references.pmid: 22795851
references.citation: Biomaterials. 2011 Aug;32(22):5206-12
references.pmid: 21492934
references.citation: Nat Rev Immunol. 2008 Jul;8(7):559-68
references.pmid: 18575461
references.citation: J Control Release. 2005 Nov 28;108(2-3):226-36
references.pmid: 16125267
references.citation: Chem Rec. 2005;5(6):352-66
references.pmid: 16278834
references.citation: Infect Immun. 1998 Nov;66(11):5089-98
references.pmid: 9784508
references.citation: Cancer Immunol Immunother. 2009 Nov;58(11):1781-94
references.pmid: 19294383
references.citation: J Biol Chem. 2002 Apr 26;277(17):15107-12
references.pmid: 11842086
references.citation: PLoS Med. 2006 Feb;3(2):e27
references.pmid: 16379499
references.citation: Nat Immunol. 2002 Apr;3(4):354-9
references.pmid: 11912497
references.citation: J Biol Chem. 2005 Mar 25;280(12):11347-51
references.pmid: 15644310
references.citation: Antiviral Res. 2012 Apr;94(1):98-102
references.pmid: 22401806
references.citation: J Viral Hepat. 2009 Oct;16(10):697-704
references.pmid: 19243496
references.citation: Nat Biotechnol. 2008 May;26(5):561-9
references.pmid: 18438401
references.citation: Virus Res. 2011 Feb;155(2):406-14
references.pmid: 21144873
references.citation: J Transl Med. 2010 Dec 21;8:138
references.pmid: 21172039
references.citation: Biomaterials. 2012 Apr;33(11):3306-15
references.pmid: 22281422
references.citation: J Exp Med. 2008 Jul 7;205(7):1601-10
references.pmid: 18591409
references.citation: Nat Immunol. 2005 Jun;6(6):565-70
references.pmid: 15895089
references.citation: Innate Immun. 2012 Oct;18(5):700-8
references.pmid: 22330637
references.citation: J Biol Chem. 2002 Dec 6;277(49):47834-43
references.pmid: 12324469
references.citation: Nature. 2009 Apr 30;458(7242):1191-5
references.pmid: 19252480
references.citation: J Virol. 2006 Jan;80(2):866-74
references.pmid: 16378988
references.citation: Clin Diagn Lab Immunol. 2004 May;11(3):483-95
references.pmid: 15138173
references.citation: Nat Rev Cancer. 2009 Jan;9(1):57-63
references.pmid: 19052556
references.citation: J Biol Chem. 2001 Jun 15;276(24):21129-35
references.pmid: 11274165
references.citation: Lancet. 2003 Jul 26;362(9380):293-4
references.pmid: 12892961
references.citation: Biochem Biophys Res Commun. 2008 Mar 28;368(1):94-9
references.pmid: 18222170
references.citation: J Exp Med. 1999 Jun 7;189(11):1777-82
references.pmid: 10359581
references.citation: Immunology. 2012 May;136(1):64-77
references.pmid: 22260507
references.citation: Nat Immunol. 2008 Apr;9(4):361-8
references.pmid: 18297073
references.citation: Antiviral Res. 2011 Jul;91(1):1-10
references.pmid: 21549154
references.citation: J Antimicrob Chemother. 2012 Jan;67(1):49-58
references.pmid: 22076990
references.citation: Nat Rev Immunol. 2012 Feb 03;12(3):168-79
references.pmid: 22301850
references.citation: Cancer Res. 2004 Aug 1;64(15):5461-70
references.pmid: 15289356
references.citation: Innate Immun. 2011 Oct;17(5):427-38
references.pmid: 20682588
references.citation: Annu Rev Biochem. 2002;71:635-700
references.pmid: 12045108
references.citation: J Immunol. 2007 Jul 15;179(2):775-80
references.pmid: 17617566
references.citation: Cell. 2006 Jun 2;125(5):943-55
references.pmid: 16751103
references.citation: J Viral Hepat. 2011 Jul;18(7):e298-306
references.pmid: 21692941
references.citation: J Immunol. 2000 Oct 15;165(8):4272-80
references.pmid: 11035061
references.citation: Nat Med. 2005 Jul;11(7):791-6
references.pmid: 15951748
references.citation: Immunity. 2002 Sep;17(3):251-63
references.pmid: 12354379
references.citation: Nat Immunol. 2002 Jul;3(7):667-72
references.pmid: 12055629
references.citation: Cell. 2011 Nov 11;147(4):868-80
references.pmid: 22078883
references.citation: J Biol Chem. 2004 Jun 18;279(25):26307-13
references.pmid: 15096514