TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons.
Immunology
Infectious disease
Innate immunity
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
04 01 2021
04 01 2021
Historique:
received:
24
10
2019
accepted:
05
11
2020
entrez:
4
1
2021
pubmed:
5
1
2021
medline:
9
9
2021
Statut:
ppublish
Résumé
Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity.
Identifiants
pubmed: 33393505
pii: 134529
doi: 10.1172/JCI134529
pmc: PMC7773389
doi:
pii:
Substances chimiques
TLR3 protein, human
0
TLR3 protein, mouse
0
Toll-Like Receptor 3
0
Interferon-beta
77238-31-4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : MRF
ID : MRF_C0483
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS072381
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI151663
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI088364
Pays : United States
Organisme : Medical Research Council
ID : MR/S032304/1
Pays : United Kingdom
Références
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Cell. 2020 Jun 11;181(6):1194-1199
pubmed: 32405102
J Exp Med. 2008 Jul 7;205(7):1601-10
pubmed: 18591409
Cell. 2005 Sep 9;122(5):669-82
pubmed: 16125763
J Leukoc Biol. 1997 May;61(5):567-74
pubmed: 9129205
Nature. 2016 May 5;533(7601):125-9
pubmed: 27120160
Mol Cell. 2005 Jan 7;17(1):93-102
pubmed: 15629720
Blood. 2009 Feb 12;113(7):1399-407
pubmed: 18757776
Bioinformatics. 2012 Aug 15;28(16):2184-5
pubmed: 22743226
PLoS One. 2009;4(1):e4127
pubmed: 19122812
Annu Rev Microbiol. 2013;67:355-74
pubmed: 24024635
Eur J Paediatr Neurol. 2008 Mar;12(2):72-81
pubmed: 17870623
Genes Immun. 2015 Dec;16(8):552-66
pubmed: 26513235
J Immunol. 2006 Feb 1;176(3):1937-42
pubmed: 16424225
Immunity. 2005 Jul;23(1):19-28
pubmed: 16039576
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3516-21
pubmed: 14993594
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Mol Cell. 2005 Sep 16;19(6):727-40
pubmed: 16153868
J Immunol. 2008 Jan 1;180(1):483-91
pubmed: 18097050
Cancer Res. 2006 Apr 15;66(8):4468-77
pubmed: 16618774
PLoS Pathog. 2006 Jun;2(6):e53
pubmed: 16789835
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64
pubmed: 16714379
Genome Biol. 2014;15(12):550
pubmed: 25516281
Science. 2006 Oct 13;314(5797):308-12
pubmed: 16973841
Curr Opin Allergy Clin Immunol. 2007 Dec;7(6):495-505
pubmed: 17989525
Science. 2020 Oct 23;370(6515):
pubmed: 32972995
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20446-51
pubmed: 19074283
J Biol Chem. 2004 Mar 26;279(13):12542-50
pubmed: 14729660
Nature. 2000 May 25;405(6785):466-72
pubmed: 10839543
Annu Rev Med. 2017 Jan 14;68:297-315
pubmed: 27813875
J Clin Invest. 2021 Jan 4;131(1):
pubmed: 32960813
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
Nat Immunol. 2010 May;11(5):373-84
pubmed: 20404851
Nature. 2001 Oct 18;413(6857):732-8
pubmed: 11607032
Mol Cell. 2000 Nov;6(5):1243-52
pubmed: 11106761
FEBS Lett. 1998 Dec 11;441(1):106-10
pubmed: 9877175
Immunity. 2017 May 16;46(5):875-890.e6
pubmed: 28514692
Nature. 2008 Mar 13;452(7184):234-8
pubmed: 18305481
Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8342-8347
pubmed: 28716935
J Exp Med. 2011 Sep 26;208(10):2083-98
pubmed: 21911422
Neurology. 2014 Nov 18;83(21):1888-97
pubmed: 25339207
J Exp Med. 2019 Sep 2;216(9):2038-2056
pubmed: 31217193
J Exp Med. 2012 Aug 27;209(9):1567-82
pubmed: 22851595
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
J Allergy Clin Immunol. 2017 Jun;139(6):1995-1997.e9
pubmed: 28087227
Science. 2020 Oct 23;370(6515):
pubmed: 32972996
Nat Immunol. 2006 Feb;7(2):156-64
pubmed: 16415873
Nature. 2014 Jan 30;505(7485):691-5
pubmed: 24284630
J Exp Med. 2008 Oct 27;205(11):2609-21
pubmed: 18838547
Virus Res. 2001 Jul;76(1):87-102
pubmed: 11376849
Science. 2015 Apr 24;348(6233):448-53
pubmed: 25814066
J Immunol. 2010 Jun 15;184(12):6929-37
pubmed: 20483774
J Interferon Cytokine Res. 2009 Sep;29(9):499-509
pubmed: 19715459
Bioinformatics. 2016 Oct 1;32(19):3047-8
pubmed: 27312411
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Trends Mol Med. 2018 Aug;24(8):658-668
pubmed: 30060835
J Exp Med. 2017 Jul 3;214(7):1949-1972
pubmed: 28606988
J Clin Invest. 2011 Dec;121(12):4889-902
pubmed: 22105173
Virology. 2010 Oct 25;406(2):202-11
pubmed: 20692676
J Virol. 1997 Jan;71(1):371-7
pubmed: 8985359
Immunity. 2018 May 15;48(5):911-922.e7
pubmed: 29768176
Immunity. 2000 Oct;13(4):539-48
pubmed: 11070172
Nat Immunol. 2005 Oct;6(10):981-8
pubmed: 16127453
J Immunol. 2006 Nov 1;177(9):6301-7
pubmed: 17056560
Immunity. 2000 Nov;13(5):643-55
pubmed: 11114377
Genome Res. 2012 Sep;22(9):1760-74
pubmed: 22955987
Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15625-30
pubmed: 20713712
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
J Allergy Clin Immunol. 2011 Sep;128(3):610-7.e1-4
pubmed: 21722947
Nat Med. 2012 Aug;18(8):1286-90
pubmed: 22772463
Immunity. 2006 Sep;25(3):373-81
pubmed: 16979569
Nat Genet. 2003 Mar;33(3):388-91
pubmed: 12590259
Sci Transl Med. 2015 Sep 30;7(307):307ra154
pubmed: 26424569
Proc Natl Acad Sci U S A. 1984 Jan;81(2):602-6
pubmed: 6320197
J Virol. 2008 Nov;82(21):10349-58
pubmed: 18715906
Nature. 2012 Nov 29;491(7426):769-73
pubmed: 23103873
J Exp Med. 2019 Sep 2;216(9):2057-2070
pubmed: 31270247
J Cell Biol. 2007 Apr 23;177(2):265-75
pubmed: 17452530
J Infect Dis. 2017 May 1;215(9):1430-1434
pubmed: 28368532
Science. 2013 Sep 20;341(6152):1390-4
pubmed: 23989956
Immunity. 2010 Sep 24;33(3):400-11
pubmed: 20832341
Mol Biol Rep. 2012 Dec;39(12):10013-7
pubmed: 22752806
Nature. 2006 May 4;441(7089):101-5
pubmed: 16625202
J Immunol. 2006 Apr 15;176(8):5078-83
pubmed: 16585605
J Exp Med. 2017 May 1;214(5):1547-1555
pubmed: 28420733
J Exp Med. 2018 Oct 1;215(10):2567-2585
pubmed: 30143481
Science. 2000 Jun 30;288(5475):2357-60
pubmed: 10875919
Science. 2013 Feb 15;339(6121):819-23
pubmed: 23287718
Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8775-E8782
pubmed: 30154162
Virology. 1985 Apr 30;142(2):411-5
pubmed: 2414906
Virology. 2004 May 1;322(2):231-8
pubmed: 15110521
Curr Opin Immunol. 2013 Feb;25(1):19-33
pubmed: 23290562
Science. 2007 Sep 14;317(5844):1522-7
pubmed: 17872438
J Virol. 2006 May;80(10):5059-64
pubmed: 16641297
J Oral Microbiol. 2013 Oct 25;5:
pubmed: 24167660
Nature. 2005 Oct 20;437(7062):1167-72
pubmed: 16177806
Curr Allergy Asthma Rep. 2018 Apr 21;18(5):31
pubmed: 29680987