Type I interferon induction and signaling during SARS-CoV-2 infection (Homo sapiens)

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817171781614168171533, 151581681432, 4, 9EndosomeISRESARS-CoV 2 RNAIRAK4GRL0617TLR2RIG-I (DDX58)Innate ImmunityTLR9MAVSTMPRSS2MDA5 TRIFTLR3TREML4 168NucleusIKBKEIRF3TRAF6MYD88TRAF3TBK1JAK1OAS1PKR8815PLpro (nsp3)8157, 11IFNAR1IFNAR2TYK2STAT18STAT2IRF9INF-I alpha/ betaISREISGs8OAS2OAS3nsp13ACE2TLR7TLR6TLR4MYD881616NFkB16Pro-inflammatory cytokines production16161616163, 153, 153, 1515, 16IRF3PIRF7PIRF3PIRF3PINF-I alpha/ beta15, 1616SARS-CoV 2 RNA1616ACE216INF-I alpha/ betansp1STAT1PSTAT2Pnsp13nsp103nsp14nsp15nsp1633333333orf3aorf63azithromycin31012, 131, 5, 6


The induction of Type I interferons and signaling is the first response leading to the innate immune reactions during SARS-COV-2 infection. The virus can enter host cells through two mechanisms. If it enters the cell via diffusion mediated by TMPRSS2, the virus ssRNA will be detected by RIG-I and MDA5 in the cytosol. If the virus enters the cell via endocytosis, the spike proteins will be processed by CTSL in the lysosome leading to the detection of ssRNA by TLR3,7 and 9 (PMID 33506952). The extracellular virus can also be detected by TLR2,4 and 6 (PMID 33506952). The higher production of TLR4 in men and the presence of TLR7 on the X chromosome may contribute to the different responses between women and men during SARS-CoV 2 infection (PMID 33506952). TLR7 MYD88-dependent signaling is inhibited at multiple steps by the SARS-CoV Papain-Like Protease (PLpro) domain of nsp3 (red oval). The signaling pathway is critical to induction of type I interferons (INF-I) via IRF3, AP-1 and NFkB transcription factors. INF-I triggers the JAK/STAT pathway leading to the induction of interferon-stimulated genes (ISGs), such as OAS and PKR, which go one to conduct the innate immune response. TREML4 has been shown to be necessary for MYD88 recruitment by TLR7 and STAT1 participation. The inhibition of SARS-CoV-2 PLpro by GRL0617 is proposed based on Ratia, et al. 2008 and 100% sequence identity between SARS-CoV and SARS-CoV-2 across all 13 residues of PLpro involved in binding GRL0617 (82.9% identity across 316 amino acids) as determined by the alignment of RefSeq YP_009725299.1 and PDB 3E9S (https://alexanderpico.github.io/SARS-CoV-2_Alignments/#Nsp3_PLpro_domain). The antimicrobial agent, azithromycin, is in clincal trials as COVID-19 therapy in combination with hydroxychloroquine (Gautret 2020) has been shown to modulate inflammation by inhibiting the activation of many of these same transcription factors.

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  1. Yamauchi K, Shibata Y, Kimura T, Abe S, Inoue S, Osaka D, Sato M, Igarashi A, Kubota I; ''Azithromycin suppresses interleukin-12p40 expression in lipopolysaccharideand interferon-gamma stimulated macrophages.''; Int J Biol Sci, 2009 PubMed Europe PMC Scholia
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125361view23:49, 6 February 2023AlexanderPicostarndardized colors, shapes, edges and labels; tidying up
124657view13:31, 18 November 2022NhungPupdate viral proteins shapes and remove legend
124431view12:46, 27 October 2022Mkutmonlower case SARS-CoV-2 protein names
120021view10:34, 15 October 2021FinterlyReverted to version '06:31, 6 June 2021' by Finterly
120006view04:41, 11 October 2021FinterlyChanged some of the "P" shapes to states.
118978view06:31, 6 June 2021EgonwTranslocation
118875view12:03, 3 June 2021EweitzOntology Term : 'COVID-19' added !
116599view19:13, 8 May 2021EweitzModified title
116223view09:42, 21 April 2021DeSlConnected "necessary stimulation was from TREMBL4 to the MYD88 recruitment by TLR7", and "inhibition STAT1 by nsp1"
116205view15:08, 19 April 2021AnnaNiCorrect node IDs, update references, confirm TLR3 and TLR7 pathways
116204view15:01, 19 April 2021DeSlUpdated database annotations for ORF6 and ORF3a from Swissprot to trembl
116155view10:24, 14 April 2021NhungPAdd TREML4 identifier and references
116153view08:53, 14 April 2021NhungPModified description
116152view08:41, 14 April 2021NhungPModified description
116151view08:23, 14 April 2021NhungPAdd axithromycin. Adjust layout
116143view13:16, 13 April 2021NhungPAdd SARS-CoV 2 proteins
116142view12:52, 13 April 2021NhungPAdjust layout. remove NFkB cytokine production pathway
116133view08:33, 13 April 2021NhungPAdd phosphorylated IRF3/7 dimer and IFN 1 alpha beta
116082view17:01, 9 April 2021NhungPAdd RIG-I, MDA5 and corresponding references. Working progress, don't remove
116079view10:28, 9 April 2021NhungPAdd tlr2,6,4, their cascades, and references. Work in progress. don't remove
116076view07:51, 9 April 2021NhungPUpdate literature
116061view14:25, 7 April 2021NhungPFix TLRs for 2 types of virus entry: diffusion and endocytosis. Working progress, don't remove
115857view15:52, 18 March 2021NhungPAdd references to interactions
115853view15:37, 18 March 2021NhungPUpdate nsp13-TBK1 interaction to inhibition. Corresponding literatures were also added to this inhibition
111110view09:08, 13 July 2020EgonwMake the linked pathway clickable (tho no identifier)
110206view10:53, 24 April 2020Fehrhartadded legend
110201view20:40, 23 April 2020EgonwTyped proteins as Type="Protein"
109974view18:19, 8 April 2020AlexanderPicoupdated sars nodes per #covidpathways guidelines
109832view23:31, 1 April 2020AlexanderPicoadded lit ref for clinical trial; removed stray datanode
109831view23:30, 1 April 2020AlexanderPicoModified description
109830view23:18, 1 April 2020AlexanderPicoAdded azithromycin
109785view00:54, 1 April 2020AlexanderPicoModified description
109763view02:05, 31 March 2020AlexanderPicoModified description
109762view21:15, 30 March 2020AlexanderPicoAdded nsp13 interaction and lit ref
109694view01:13, 29 March 2020AlexanderPicoModified description
109693view00:58, 29 March 2020AlexanderPicoModified title
109692view00:58, 29 March 2020AlexanderPicoUpdate to Ensembl IDs and HGNC labels
109691view00:49, 29 March 2020AlexanderPicoAdded RefSeq ID for PLpro(nsp3)
109690view00:35, 29 March 2020AlexanderPicoClarified NFKB
109689view00:14, 29 March 2020AlexanderPicoLayout tweaks
109688view00:08, 29 March 2020AlexanderPicoLayout tweaks; fixed TRAF6 path
109685view23:40, 28 March 2020AlexanderPicoAdded another ref for inhibition of PLpro by GRL0617
109684view23:37, 28 March 2020AlexanderPicoOntology Term : 'severe acute respiratory syndrome' added !
109683view23:37, 28 March 2020AlexanderPicoOntology Term : 'viral infectious disease' added !
109682view23:37, 28 March 2020AlexanderPicoOntology Term : 'signaling pathway' added !
109681view23:36, 28 March 2020AlexanderPicoOntology Term : 'type I interferon signaling pathway' added !
109680view22:56, 28 March 2020AlexanderPicoModified description
109679view22:50, 28 March 2020AlexanderPicoAdded lit refs
109677view22:43, 28 March 2020AlexanderPicoNew pathway

External references


View all...
NameTypeDatabase referenceComment
ACE2GeneProductQ9BYF1 (Uniprot-TrEMBL)
GRL0617MetaboliteQ27097846 (Wikidata)
IFNAR1GeneProductENSG00000142166 (Ensembl)
IFNAR2GeneProductENSG00000159110 (Ensembl)
IKBKEGeneProductENSG00000263528 (Ensembl)
INF-I alpha/ betaProteinQ6046488 (Wikidata)
IRAK4ProteinENSG00000198001 (Ensembl)
IRF3GeneProductENSG00000126456 (Ensembl)
IRF7GeneProductENSG00000185507 (Ensembl)
IRF9GeneProductENSG00000213928 (Ensembl)
Innate ImmunityPathway
JAK1GeneProductENSG00000162434 (Ensembl)
MAVSProteinENSG00000088888 (Ensembl)
MDA5 ProteinENSG00000115267 (Ensembl)
MYD88GeneProductENSG00000172936 (Ensembl)
OAS1GeneProductENSG00000089127 (Ensembl)
OAS2GeneProductENSG00000111335 (Ensembl)
OAS3GeneProductENSG00000111331 (Ensembl)
PKRGeneProductENSG00000055332 (Ensembl)
PLpro (nsp3)ProteinYP_009725299.1 (RefSeq)
Pro-inflammatory cytokines productionPathway
RIG-I (DDX58)ProteinENSG00000107201 (Ensembl)
SARS-CoV 2 RNARnaQ82069695 (Wikidata)
STAT1GeneProductENSG00000115415 (Ensembl)
STAT2GeneProductENSG00000170581 (Ensembl)
TBK1GeneProductENSG00000183735 (Ensembl)
TLR2ProteinO60603 (Uniprot-TrEMBL)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TLR4ProteinO00206 (Uniprot-TrEMBL)
TLR6ProteinQ9Y2C9 (Uniprot-TrEMBL)
TLR7GeneProductENSG00000196664 (Ensembl)
TLR9ProteinQ9NR96 (Uniprot-TrEMBL)
TMPRSS2ProteinO15393 (Uniprot-TrEMBL)
TRAF3GeneProductENSG00000131323 (Ensembl)
TRAF6GeneProductENSG00000175104 (Ensembl)
TREML4 ProteinQ6UXN2 (Uniprot-TrEMBL)
TRIF Protein
TYK2GeneProductENSG00000105397 (Ensembl)
azithromycinMetaboliteQ165399 (Wikidata)
nsp10ProteinYP_009725306 (NCBI Protein) PDB structure for SARS-CoV strain: 6JYT
nsp13ProteinQII57165.1 (RefSeq) PDB structure for SARS-CoV strain: 6JYT
nsp14ProteinYP_009725309 (NCBI Protein) PDB structure for SARS-CoV strain: 6JYT
nsp15ProteinYP_009725310 (NCBI Protein) PDB structure for SARS-CoV strain: 6JYT
nsp16ProteinYP_009725311 (NCBI Protein) PDB structure for SARS-CoV strain: 6JYT
nsp1ProteinYP_009725297 (NCBI Protein) PDB structure for SARS-CoV strain: 6JYT
orf3aProteinP0DTC3 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
orf6ProteinP0DTC6 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT

Annotated Interactions

No annotated interactions

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