Type I interferon induction and signaling during SARS-CoV-2 infection (WP4868)

Homo sapiens

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.


Alex Pico , Egon Willighagen , Friederike Ehrhart , Nhung Pham , Denise Slenter , Anna Niarakis , Eric Weitz , Finterly Hu , and Martina Summer-Kutmon


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Homo sapiens




Disease Ontology

COVID-19 severe acute respiratory syndrome viral infectious disease

Pathway Ontology

type I interferon signaling pathway signaling pathway


Label Type Compact URI Comment
GRL0617 Metabolite wikidata:Q27097846
azithromycin Metabolite wikidata:Q165399
IKBKE GeneProduct ensembl:ENSG00000263528
IRF3 GeneProduct ensembl:ENSG00000126456
TRAF6 GeneProduct ensembl:ENSG00000175104
MYD88 GeneProduct ensembl:ENSG00000172936
TRAF3 GeneProduct ensembl:ENSG00000131323
TBK1 GeneProduct ensembl:ENSG00000183735
JAK1 GeneProduct ensembl:ENSG00000162434
OAS1 GeneProduct ensembl:ENSG00000089127
PKR GeneProduct ensembl:ENSG00000055332
IFNAR1 GeneProduct ensembl:ENSG00000142166
IFNAR2 GeneProduct ensembl:ENSG00000159110
TYK2 GeneProduct ensembl:ENSG00000105397
STAT1 GeneProduct ensembl:ENSG00000115415
STAT2 GeneProduct ensembl:ENSG00000170581
IRF9 GeneProduct ensembl:ENSG00000213928
OAS2 GeneProduct ensembl:ENSG00000111335
OAS3 GeneProduct ensembl:ENSG00000111331
ACE2 GeneProduct uniprot:Q9BYF1
TLR7 GeneProduct ensembl:ENSG00000196664
MYD88 GeneProduct ensembl:ENSG00000172936
IRF3 GeneProduct ensembl:ENSG00000126456
IRF7 GeneProduct ensembl:ENSG00000185507
IRF3 GeneProduct ensembl:ENSG00000126456
IRF3 GeneProduct ensembl:ENSG00000126456
ACE2 GeneProduct uniprot:Q9BYF1
STAT1 GeneProduct ensembl:ENSG00000115415
STAT2 GeneProduct ensembl:ENSG00000170581
TLR3 Protein uniprot:O15455
TLR9 Protein uniprot:Q9NR96
MDA5 Protein ensembl:ENSG00000115267
TREML4 Protein uniprot:Q6UXN2
RIG-I (DDX58) Protein ensembl:ENSG00000107201
TMPRSS2 Protein uniprot:O15393
TLR2 Protein uniprot:O60603
IRAK4 Protein ensembl:ENSG00000198001
MAVS Protein ensembl:ENSG00000088888
PLpro (nsp3) Protein refseq:YP_009725299.1
INF-I alpha/ beta Protein wikidata:Q6046488
nsp13 Protein refseq:QII57165.1 PDB structure for SARS-CoV strain: 6JYT
TLR6 Protein uniprot:Q9Y2C9
TLR4 Protein uniprot:O00206
INF-I alpha/ beta Protein wikidata:Q6046488
INF-I alpha/ beta Protein wikidata:Q6046488
nsp1 Protein ncbiprotein:YP_009725297 PDB structure for SARS-CoV strain: 6JYT
nsp1 Protein ncbiprotein:YP_009725297 PDB structure for SARS-CoV strain: 6JYT
nsp10 Protein ncbiprotein:YP_009725306 PDB structure for SARS-CoV strain: 6JYT
nsp14 Protein ncbiprotein:YP_009725309 PDB structure for SARS-CoV strain: 6JYT
nsp15 Protein ncbiprotein:YP_009725310 PDB structure for SARS-CoV strain: 6JYT
nsp16 Protein ncbiprotein:YP_009725311 PDB structure for SARS-CoV strain: 6JYT
orf3a Protein uniprot:P0DTC3 PDB structure for SARS-CoV strain: 6JYT
orf6 Protein uniprot:P0DTC6 PDB structure for SARS-CoV strain: 6JYT


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