Type I Interferon Induction and Signaling During SARS-CoV-2 Infection (Homo sapiens)

From WikiPathways

Jump to: navigation, search


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 (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.

Quality Tags

Ontology Terms



View all...
  1. 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
  2. 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
  3. 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
  4. Fung TS, Liu DX; ''Human Coronavirus: Host-Pathogen Interaction.''; Annu Rev Microbiol, 2019 PubMed Europe PMC Scholia
  5. 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
  6. Gordon, DE, Jang, GM, Bouhaddou, M, Xu J; ''A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing''; BioRxiv, 2020
  7. 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
  8. 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


View all...
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
CHUKGeneProductENSG00000213341 (Ensembl)
FOSGeneProductENSG00000170345 (Ensembl) NFKB not specified
GRL0617MetaboliteQ27097846 (Wikidata)
IFNAR1GeneProductENSG00000142166 (Ensembl)
IFNAR2GeneProductENSG00000159110 (Ensembl)
IKBKBGeneProductENSG00000104365 (Ensembl)
IKBKEGeneProductENSG00000263528 (Ensembl)
IKBKGGeneProductENSG00000269335 (Ensembl)
IRF3GeneProductENSG00000126456 (Ensembl)
IRF9GeneProductENSG00000213928 (Ensembl)
Innate ImmunityPathway
JAK1GeneProductENSG00000162434 (Ensembl)
JUNGeneProductENSG00000177606 (Ensembl) NFKB not specified
MAP3K7GeneProductENSG00000135341 (Ensembl)
MAPK14GeneProductENSG00000112062 (Ensembl)
MAPK8GeneProductENSG00000107643 (Ensembl)
MYD88GeneProductENSG00000172936 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl) NFKB not specified
NFKBIAGeneProductENSG00000100906 (Ensembl)
OAS1GeneProductENSG00000089127 (Ensembl)
OAS2GeneProductENSG00000111335 (Ensembl)
OAS3GeneProductENSG00000111331 (Ensembl)
PKRGeneProductENSG00000055332 (Ensembl)
PLpro (nsp3)ProteinYP_009725299.1 (RefSeq)
STAT1GeneProductENSG00000115415 (Ensembl)
STAT2GeneProductENSG00000170581 (Ensembl)
TBK1GeneProductENSG00000183735 (Ensembl)
TLR7GeneProductENSG00000196664 (Ensembl)
TRAF3GeneProductENSG00000131323 (Ensembl)
TRAF6GeneProductENSG00000175104 (Ensembl)
TREML4GeneProductENSG00000188056 (Ensembl) TRAM not specified
TYK2GeneProductENSG00000105397 (Ensembl)
azithromycinMetaboliteQ165399 (Wikidata)
nsp13ProteinQII57165.1 (RefSeq) PDB structure for SARS-CoV strain: 6JYT

Annotated Interactions

No annotated interactions

Personal tools