Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia.
RNA
SARS-CoV-2
iPSC-derived human microglia
inflammatory response
macrophages
toll-like receptors
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2022
2022
Historique:
received:
10
10
2022
accepted:
23
12
2022
entrez:
30
1
2023
pubmed:
31
1
2023
medline:
1
2
2023
Statut:
epublish
Résumé
The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is marked by thromboembolic events and an inflammatory response throughout the body, including the brain. Employing the machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate the viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells we tested such RNA fragments with respect to their potential to induce activation of human TLR7 and TLR8 and to activate human macrophages, as well as iPSC-derived human microglia, the resident immune cells in the brain. We experimentally validated several sequence-specific RNA fragment candidates out of the SARS-CoV-2 RNA fragments predicted in silico as activators of human TLR7 and TLR8. Moreover, these SARS-CoV-2 ssRNAs induced cytokine release from human macrophages and iPSC-derived human microglia in a sequence- and species-specific fashion. Our findings determine TLR7 and TLR8 as key sensors of SARS-CoV-2-derived ssRNAs and may deepen our understanding of the mechanisms how this virus triggers, but also modulates an inflammatory response through innate immune signaling.
Identifiants
pubmed: 36713399
doi: 10.3389/fimmu.2022.1066456
pmc: PMC9880480
doi:
Substances chimiques
Cytokines
0
RNA, Viral
0
Toll-Like Receptor 7
0
Toll-Like Receptor 8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1066456Informations de copyright
Copyright © 2023 Wallach, Raden, Hinkelmann, Brehm, Rabsch, Weidling, Krüger, Kettenmann, Backofen and Lehnardt.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Cell. 2020 Dec 10;183(6):1520-1535.e14
pubmed: 33157038
Cells. 2020 Jan 11;9(1):
pubmed: 31940779
Annu Rev Physiol. 2017 Feb 10;79:619-643
pubmed: 27959620
Mol Neurodegener. 2018 Dec 22;13(1):67
pubmed: 30577865
Cell. 2019 Nov 27;179(6):1264-1275.e13
pubmed: 31778653
Nat Neurosci. 2021 Feb;24(2):168-175
pubmed: 33257876
RNA Biol. 2021 Oct 15;18(sup1):268-277
pubmed: 34241565
J Bioinform Comput Biol. 2019 Oct;17(5):1940009
pubmed: 31856671
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Cell Rep. 2018 Dec 18;25(12):3371-3381.e5
pubmed: 30566863
Microbes Infect. 2013 Feb;15(2):88-95
pubmed: 23123977
Pharmacol Res Perspect. 2021 Oct;9(5):e00842
pubmed: 34414672
Cell Rep. 2022 Apr 12;39(2):110670
pubmed: 35417708
Microbes Infect. 2020 May - Jun;22(4-5):226-229
pubmed: 32361001
JCI Insight. 2020 Apr 9;5(7):
pubmed: 32271161
J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
pubmed: 12430718
Algorithms Mol Biol. 2011 Nov 24;6:26
pubmed: 22115189
Nat Cell Biol. 2021 Jul;23(7):682-683
pubmed: 34239063
Int Immunol. 2016 May;28(5):211-22
pubmed: 26489884
Acta Neuropathol Commun. 2020 Feb 18;8(1):19
pubmed: 32070434
PLoS Pathog. 2021 Jan 19;17(1):e1009212
pubmed: 33465165
Science. 2004 Mar 5;303(5663):1526-9
pubmed: 14976262
J Biol Chem. 2021 Jan-Jun;296:100306
pubmed: 33476648
Immunity. 2021 Jul 13;54(7):1594-1610.e11
pubmed: 34174183
Nat Struct Mol Biol. 2015 Feb;22(2):109-15
pubmed: 25599397
Cell Rep. 2020 Sep 22;32(12):108175
pubmed: 32946807
Curr Protein Pept Sci. 2021 Oct 26;22(4):273-289
pubmed: 33749559
J Immunol. 2012 Aug 1;189(3):1448-58
pubmed: 22745379
Science. 2020 Oct 23;370(6515):
pubmed: 32972995
J Innate Immun. 2021;13(6):345-358
pubmed: 34058746
J Neurol Neurosurg Psychiatry. 2020 Aug;91(8):889-891
pubmed: 32354768
J Exp Med. 2021 Mar 1;218(3):
pubmed: 33433624
Nat Rev Immunol. 2022 Apr;22(4):224-235
pubmed: 34272507
Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):
pubmed: 34021074
Immunity. 2016 Oct 18;45(4):737-748
pubmed: 27742543
Front Immunol. 2020 Aug 13;11:1554
pubmed: 32903619
Nat Immunol. 2010 May;11(5):373-84
pubmed: 20404851
Sci Immunol. 2021 Aug 19;6(62):
pubmed: 34413140
Neuron. 2017 Apr 19;94(2):278-293.e9
pubmed: 28426964
Immunity. 2022 Jul 12;55(7):1159-1172
pubmed: 35777361
Nat Immunol. 2002 Jun;3(6):499
pubmed: 12032557
Nucleic Acids Res. 2017 Jul 3;45(W1):W435-W439
pubmed: 28472523
Microbiol Spectr. 2022 Jun 29;10(3):e0109122
pubmed: 35510852
JAMA. 2020 Aug 18;324(7):663-673
pubmed: 32706371
Nat Rev Immunol. 2020 Jun;20(6):355-362
pubmed: 32376901
JCI Insight. 2021 Sep 22;6(18):
pubmed: 34375313
J Immunol. 2004 Sep 15;173(6):3916-24
pubmed: 15356140
N Engl J Med. 2020 Jun 4;382(23):2268-2270
pubmed: 32294339
Nature. 2021 Jan;589(7840):125-130
pubmed: 32906143
Clin Immunol. 2020 Jun;215:108448
pubmed: 32353634
Cell. 2006 Feb 24;124(4):783-801
pubmed: 16497588
Lancet Neurol. 2020 Nov;19(11):919-929
pubmed: 33031735
Nat Rev Immunol. 2018 Apr;18(4):225-242
pubmed: 29151590
Int J Infect Dis. 2020 May;94:55-58
pubmed: 32251791
Lancet. 2020 Feb 15;395(10223):497-506
pubmed: 31986264
Lancet Microbe. 2020 Nov;1(7):e290-e299
pubmed: 33015653
J Neurol Sci. 2021 Nov 15;430:120023
pubmed: 34678659
Science. 2004 Mar 5;303(5663):1529-31
pubmed: 14976261
J Neurosci. 2002 Apr 1;22(7):2478-86
pubmed: 11923412
Nat Rev Mol Cell Biol. 2022 Jan;23(1):3-20
pubmed: 34611326
Environ Res. 2020 Sep;188:109858
pubmed: 32846644
Immunity. 2020 Apr 14;52(4):591-605.e6
pubmed: 32294405
PLoS One. 2013;8(3):e58808
pubmed: 23516559
Virology. 2018 Apr;517:9-15
pubmed: 29217279
EBioMedicine. 2022 May;79:103999
pubmed: 35439679
Front Pharmacol. 2022 Sep 07;13:989664
pubmed: 36188605
Nat Neurosci. 2012 Jun;15(6):827-35
pubmed: 22610069
Blood. 2009 Dec 17;114(26):5290-8
pubmed: 19850743
JAMA Neurol. 2020 Jun 1;77(6):683-690
pubmed: 32275288
Nat Commun. 2020 Oct 15;11(1):5204
pubmed: 33060576
J Immunol. 2008 Feb 15;180(4):2117-24
pubmed: 18250417