COVID-19 and endothelial cell senescence (Homo sapiens)

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913SARS-CoV 2ANO6IL17Avirus proteinTLR4ORF3aORF8


Description

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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Bibliography

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  1. Xia H, Cao Z, Xie X, Zhang X, Chen JY, Wang H, Menachery VD, Rajsbaum R, Shi PY; ''Evasion of Type I Interferon by SARS-CoV-2.''; Cell Rep, 2020 PubMed Europe PMC Scholia
  2. Xia H, Shi PY; ''Antagonism of Type I Interferon by Severe Acute Respiratory Syndrome Coronavirus 2.''; J Interferon Cytokine Res, 2020 PubMed Europe PMC Scholia
  3. 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
  4. 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
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  6. Ramirez-Ortiz ZG, Prasad A, Griffith JW, Pendergraft WF 3rd, Cowley GS, Root DE, Tai M, Luster AD, El Khoury J, Hacohen N, Means TK; ''The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity.''; Nat Immunol, 2015 PubMed Europe PMC Scholia
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  15. 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
  16. Yamauchi K, Shibata Y, Kimura T, Abe S, Inoue S, Osaka D, Sato M, Igarashi A, Kubota I; ''Azithromycin suppresses interleukin-12p40 expression in lipopolysaccharide and interferon-gamma stimulated macrophages.''; Int J Biol Sci, 2009 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
124640view12:48, 18 November 2022Jfigueirahasbunupdated viral protein labels, shapes and identifiers
124554view12:38, 8 November 2022EweitzReduce negative space at top and left of pathway graphic
124553view12:32, 8 November 2022EweitzUse name instead of ID as pathway label, fix typos, refine virus dimensions
124552view12:25, 8 November 2022EweitzModified title
124041view15:07, 14 September 2022DeSlUpdate ID for NSP4
124040view15:05, 14 September 2022DeSlChnaged MIM-conversion to Arrows
124039view15:04, 14 September 2022DeSlConverted SARS-COV2 drawing to graphical lines
123978view10:43, 9 September 2022EweitzModified title
123678view09:52, 9 August 2022EgonwNot a mim-conversion
123532view06:33, 2 August 2022EgonwMade a pathway clickable
123236view14:51, 5 July 2022LaureAlix
123235view14:48, 5 July 2022LaureAlix
123222view14:21, 5 July 2022LaureAlixModified description
123221view14:20, 5 July 2022LaureAlix
123220view14:10, 5 July 2022LaureAlix
123217view14:06, 5 July 2022LaureAlix
123215view14:03, 5 July 2022LaureAlixchanges
123209view13:39, 5 July 2022LaureAlix
123208view13:38, 5 July 2022LaureAlixNew pathway

External references

DataNodes

NameTypeDatabase referenceComment
ANO6GeneProductENSG00000177119 (Ensembl)
IL17AGeneProductENSG00000112115 (Ensembl)
ORF3aProteinP0DTC3 (Uniprot-TrEMBL) PDB structure for SARS-CoV strain: 6JYT
ORF8GeneProduct43740577 (Entrez Gene) PDB structure for SARS-CoV strain: 6JYT
TLR4ProteinO00206 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions

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