Host-pathogen interaction of human coronaviruses - interferon induction (Homo sapiens)

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Figure 8 of review. The induction of Type I interferons and signaling leading to the innate immune response during SARS-COV-2 infection. 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 ( The antimicrobial agent, azithromycin, is in clinical 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. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D; ''Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.''; Int J Antimicrob Agents, 2020 PubMed Europe PMC Scholia
  2. Edelmann MJ, Nicholson B, Kessler BM; ''Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases.''; Expert Rev Mol Med, 2011 PubMed Europe PMC Scholia
  3. Baines KJ, Wright TK, Gibson PG, Powell H, Hansbro PM, Simpson JL; ''Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD.''; ERJ Open Res, 2018 PubMed Europe PMC Scholia
  4. Fung TS, Liu DX; ''Human Coronavirus: Host-Pathogen Interaction.''; Annu Rev Microbiol, 2019 PubMed Europe PMC Scholia
  5. Gordon, DE, Jang, GM, Bouhaddou, M, Xu J; ''A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing''; Nature, 2020 PubMed Europe PMC Scholia
  6. Aghai ZH, Kode A, Saslow JG, Nakhla T, Farhath S, Stahl GE, Eydelman R, Strande L, Leone P, Rahman I; ''Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants.''; Pediatr Res, 2007 PubMed Europe PMC Scholia
  7. Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, Chaudhuri R, Fu W, Prabhakar BS, Johnson ME, Baker SC, Ghosh AK, Mesecar AD; ''A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC Scholia
  8. 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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128661view12:59, 18 February 2024EweitzFix nucleus collision, economize layout, standardize case
124638view12:43, 18 November 2022NhungPupdate viral protein shapes
124597view06:40, 13 November 2022EgonwNeeds a shape to be clickable
124596view06:39, 13 November 2022EgonwIs PAMP a protein, metabolite, ... ?
124595view06:38, 13 November 2022EgonwAdded a database identifier
124594view06:38, 13 November 2022EgonwConverted a label into a node
119113view13:32, 17 June 2021FinterlyAdded PMID
116598view19:12, 8 May 2021EweitzModified title
116364view12:37, 4 May 2021EweitzModified title
114076view06:26, 21 December 2020EgonwConverted three labels into DataNodes.
111157view08:43, 21 July 2020EgonwMade the pathway clickable
110825view09:55, 10 June 2020FehrhartModified description
110596view06:57, 20 May 2020FehrhartReverted to version '06:56, 30 April 2020' by Fehrhart
110504view08:56, 15 May 2020EveloModified title
110249view06:56, 30 April 2020Fehrhartadded a few IDs
110209view13:06, 24 April 2020EgonwTyped proteins as Type="Protein"
110025view19:35, 12 April 2020AlexanderPicoConnected interaction
109979view18:21, 8 April 2020AlexanderPicoupdated sars nodes per #covidpathways guidelines
109952view18:34, 7 April 2020EgonwAdded an identifier
109874view09:16, 3 April 2020Fehrhartwork in progress
109873view08:46, 3 April 2020Fehrhartwork in progress
109871view07:55, 3 April 2020FehrhartModified description
109859view14:55, 2 April 2020Fehrhartwork in progress
109858view14:35, 2 April 2020FehrhartNew pathway

External references


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NameTypeDatabase referenceComment
3aProteinP59632 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
3bProteinP59633 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
4aProteinPDB structure for SARS-CoV strain: 6JYT
4bProteinPDB structure for SARS-CoV strain: 6JYT
6ProteinP59634 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
7aProteinP59635 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
8abProteinPDB structure for SARS-CoV strain: 6JYT
8bProteinPDB structure for SARS-CoV strain: 6JYT
9bProteinP59636 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
CHUKGeneProductENSG00000213341 (Ensembl) IKKα, IκB kinase α
DDX58GeneProductENSG00000107201 (Ensembl) RIG1
EProteinP59637 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
FOSGeneProductENSG00000170345 (Ensembl) NFKB not specified
IFIH1GeneProductENSG00000115267 (Ensembl) MDA5
IFNAR1GeneProductENSG00000142166 (Ensembl)
IFNAR2GeneProductENSG00000159110 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl) IKKb, IκB kinase b
IKBKEGeneProductENSG00000263528 (Ensembl)
IKBKGGeneProductENSG00000269335 (Ensembl) NEMO
IRF3GeneProductENSG00000126456 (Ensembl)
IRF9GeneProductENSG00000213928 (Ensembl)
Innate immunityPathwayWP4912 (WikiPathways)
JAK1GeneProductENSG00000162434 (Ensembl)
JUNGeneProductENSG00000177606 (Ensembl) NFKB not specified
MAP3K7GeneProductENSG00000135341 (Ensembl) TAK1
MAPK14GeneProductENSG00000112062 (Ensembl)
MAPK8GeneProductENSG00000107643 (Ensembl)
MAVSGeneProductENSG00000088888 (Ensembl)
MProteinP59596 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
MYD88GeneProductENSG00000172936 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl) NFKB not specified
NFKBIAGeneProductENSG00000100906 (Ensembl) IκBα, NF-κB inhibitor alpha
NProteinQ89457519 (Wikidata) PDB structure for SARS-CoV strain: 6JYT
OAS1GeneProductENSG00000089127 (Ensembl)
OAS2GeneProductENSG00000111335 (Ensembl)
OAS3GeneProductENSG00000111331 (Ensembl)
PAMPQ1483180 (Wikidata) Pathogen-associated molecular pattern
PKRGeneProductENSG00000055332 (Ensembl)
PLProProteinPDB structure for SARS-CoV strain: 6JYT
PLpro (nsp3)ProteinYP_009725299.1 (RefSeq)
RIPK1GeneProductENSG00000137275 (Ensembl) RIP1
S Protein694009 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
S ProteinPDB structure for SARS-CoV strain: 6JYT
STAT1GeneProductENSG00000115415 (Ensembl)
STAT2GeneProductENSG00000170581 (Ensembl)
TBK1GeneProductENSG00000183735 (Ensembl)
TICAM1GeneProduct148022 (Entrez Gene) TRIF
TLR7GeneProductENSG00000196664 (Ensembl)
TRAF3GeneProductENSG00000131323 (Ensembl)
TRAF6GeneProductENSG00000175104 (Ensembl)
TYK2GeneProductENSG00000105397 (Ensembl)
Viral RNARna
nsp15ProteinPDB structure for SARS-CoV strain: 6JYT
nsp3ProteinPDB structure for SARS-CoV strain: 6JYT

Annotated Interactions

No annotated interactions

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