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.
Authors
Alex Pico , Egon Willighagen , Friederike Ehrhart , Nhung Pham , Denise Slenter , Anna Niarakis , Eric Weitz , Finterly Hu , and Martina Summer-KutmonActivity
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Cited In
- Tissue-specific pathway activities: A retrospective analysis in COVID-19 patients (2022).
- Bioinformatics and systems-biology analysis to determine the effects of Coronavirus disease 2019 on patients with allergic asthma (2022).
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Organisms
Homo sapiensCommunities
COVID-19Annotations
Disease Ontology
COVID-19 severe acute respiratory syndrome viral infectious diseasePathway 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 |
References
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