SARS-CoV-2 and COVID-19 pathway (WP4846)

Homo sapiens

Collaborative project for curation biological processes involved in the COVID-19 disease after SARS-Cov-2 infection. It focuses on experimental evidence and plays with improved annotation of complexes and with the Evidence and Conclusion Ontology. The complexes link to EBI's Complex Portal, resulting from a collaboration with that database at the recent online ELIXIR biohackathon. Editing this pathway is (at this moment) coordinated via the wikipathways.slack.com #sarscov2 channel. Additionally, please feel free to add suggestions to the discussion page (see the tab at the top of this page). The large viral Spike protein (S or surface glycoprotein) forms trimers. It interacts with the host's ACE2 receptor to establish binding (Hoffmann et al 2020). There are suggestions for more than one cell entry mechanism, with the evidence for ACE2/TMPRSS2 entry being most clear now. Lack of expression of TMPRSS2 may explain age differences in COVID19 severity. In this mechanism, to enter the virus needs to be primed by the host protease TMPRSS2 that splits the Spike protein into 2 peptides S1 and S2. S1 contains the ACE2 receptor binding site, S2 binds to the host cell membrane which leads to membrane fusion, the start of the uptake process. The ACE2 receptor interaction was also suggested as the start of specific lung-damaging effects. Other human genes that may be involved in alternative cell uptake mechanisms include CTSL and SLC6A19.

Authors

Egon Willighagen , Lauren J. Dupuis , Chris Evelo , Alex Pico , Friederike Ehrhart , Martina Summer-Kutmon , and Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

COVID-19

Annotations

Pathway Ontology

disease pathway

Disease Ontology

COVID-19 disease by infectious agent

Participants

Label Type Compact URI Comment
25HC Metabolite chebi:42977
HDL Metabolite chebi:39025
heparan sulfate Metabolite chebi:28815
sphingosine Metabolite chebi:16393
HDL Metabolite chebi:39025
HDL Metabolite chebi:39025
cholesterol Metabolite chebi:16113
cholesterol Metabolite chebi:16113
SCARB1 GeneProduct ensembl:ENSG00000073060
SLC6A19 GeneProduct ensembl:ENSG00000174358
ACAT GeneProduct ensembl:ENSG00000075239
orf1 GeneProduct ncbigene:43740578
ORF3a GeneProduct ncbigene:43740569
ORF6 GeneProduct ncbigene:43740572
ORF7a GeneProduct ncbigene:43740573
ORF8 GeneProduct ncbigene:43740577
ORF10 GeneProduct ncbigene:43740576
nucleocapsidphosphoprotein GeneProduct ncbigene:43740575
membraneglycoprotein GeneProduct ncbigene:43740571
envelopeprotein GeneProduct ncbigene:43740570
surfaceglycoprotein GeneProduct ncbigene:43740568
orf1 GeneProduct ncbigene:43740578
ORF7b GeneProduct ncbigene:43740574
orf1 GeneProduct ncbigene:43740578
SCARB1 GeneProduct ensembl:ENSG00000073060
surfaceglycoprotein S Protein uniprot:P0DTC2
nsp1 Protein wikidata:Q90038952 Host translation inhibitor nsp1
CTSL Protein uniprot:P07711
TLR7 Protein uniprot:Q9NYK1
TMPRSS4 Protein uniprot:Q9NRS4
FURIN Protein uniprot:P09958
S2 subunit Protein wikidata:Q106020384
SARS-CoV-2proteins Protein wikidata:Q82069695
orf1a Protein uniprot:P0DTC1
TMPRSS2 Protein uniprot:O15393
orf1ab Protein uniprot:P0DTD1
ACE2 Protein uniprot:Q9BYF1
ORF3a Protein uniprot:P0DTC3
ORF6 Protein wikidata:Q89226299
ORF7a Protein wikidata:Q88658500
ORF8 Protein wikidata:Q89225654
nucleocapsidprotein Protein uniprot:P0DTC9
membraneglycoprotein Protein uniprot:P0DTC5
envelopeprotein Protein uniprot:P0DTC4
surfaceglycoprotein Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
membraneglycoprotein M Protein uniprot:P0DTC5
orf1ab Protein uniprot:P0DTD1
nsp2 Protein wikidata:Q89006922
PL2-PRO Protein wikidata:Q87917581 nsp3
3CL-PRO Protein wikidata:Q87917582
nsp4 Protein wikidata:Q90038956
nsp7 Protein wikidata:Q90038963
nsp8 Protein wikidata:Q88659350
nsp9 Protein wikidata:Q89686805
nsp10 Protein wikidata:Q87917572 nsp10
nsp12 Protein wikidata:Q94647436 RdRp
nsp13 Protein wikidata:Q94648377 Helicase
ExoN Protein wikidata:Q94648393 nsp14
nsp15 Protein wikidata:Q87917579 NendoU
nsp16 Protein wikidata:Q87917579 2'-O-methyltransferase
nsp6 Protein wikidata:Q88656943
nsp5 Protein wikidata:Q87917582
nucleocapsidprotein N Protein uniprot:P0DTC9
envelopeprotein E Protein uniprot:P0DTC4
ORF10 Protein wikidata:Q89227548
nsp9 Protein wikidata:Q89686805
nsp9 Protein wikidata:Q89686805
ORF7b Protein wikidata:Q88089438
nsp16 Protein wikidata:Q87917579 2'-O-methyltransferase
nsp10 Protein wikidata:Q87917572 nsp10
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
ACE2 Protein uniprot:Q9BYF1
PL2-PRO Protein wikidata:Q87917581 nsp3
nsp4 Protein wikidata:Q90038956
nsp6 Protein wikidata:Q88656943
ACE2 Protein uniprot:Q9BYF1
ORF3a Protein uniprot:P0DTC3
nsp9 Protein wikidata:Q89686805
nsp10 Protein wikidata:Q87917572 nsp10
nsp1 Protein wikidata:Q90038952 Host translation inhibitor nsp1
ORF14 Protein uniprot:P0DTD3
S2 subunit Protein wikidata:Q106020384
nsp8 Protein wikidata:Q88659350
NRP1 Protein uniprot:O14786
nsp7 Protein wikidata:Q90038963
nsp8 Protein wikidata:Q88659350
nsp12 Protein wikidata:Q94647436 RdRp
orf1ab Protein uniprot:P0DTD1
orf1ab Protein uniprot:P0DTD1
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
ACE2 Protein uniprot:Q9BYF1
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
ACE2 Protein uniprot:Q9BYF1
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2
surfaceglycoprotein S Protein uniprot:P0DTC2

References

  1. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. mBio. 2013 Aug 13;4(4):e00524-13. PubMed Europe PMC Scholia
  2. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Intensive Care Med. 2020 Apr;46(4):586–90. PubMed Europe PMC Scholia
  3. A potential role for integrins in host cell entry by SARS-CoV-2. Sigrist CJ, Bridge A, Le Mercier P. Antiviral Res. 2020 May;177:104759. PubMed Europe PMC Scholia
  4. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 2020 Mar 27;367(6485):1444–8. PubMed Europe PMC Scholia
  5. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. Cell. 2020 Apr 16;181(2):271-280.e8. PubMed Europe PMC Scholia
  6. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Cell. 2020 Apr 16;181(2):281-292.e6. PubMed Europe PMC Scholia
  7. From SARS and MERS CoVs to SARS-CoV-2: Moving toward more biased codon usage in viral structural and nonstructural genes. Kandeel M, Ibrahim A, Fayez M, Al-Nazawi M. J Med Virol. 2020 Jun;92(6):660–6. PubMed Europe PMC Scholia
  8. Genetic evolution analysis of 2019 novel coronavirus and coronavirus from other species. Li C, Yang Y, Ren L. Infect Genet Evol. 2020 Aug;82:104285. PubMed Europe PMC Scholia
  9. Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Shannon A, Le NTT, Selisko B, Eydoux C, Alvarez K, Guillemot JC, et al. Antiviral Res. 2020 Jun;178:104793. PubMed Europe PMC Scholia
  10. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. Pachetti M, Marini B, Benedetti F, Giudici F, Mauro E, Storici P, et al. J Transl Med. 2020 Apr 22;18(1):179. PubMed Europe PMC Scholia
  11. Cell entry mechanisms of SARS-CoV-2. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Proc Natl Acad Sci U S A. 2020 May 26;117(21):11727–34. PubMed Europe PMC Scholia
  12. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. Sci Immunol. 2020 May 13;5(47):eabc3582. PubMed Europe PMC Scholia
  13. Structure of replicating SARS-CoV-2 polymerase. Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Nature. 2020 Aug;584(7819):154–6. PubMed Europe PMC Scholia
  14. Simultaneous Treatment of COVID-19 With Serine Protease Inhibitor Camostat and/or Cathepsin L Inhibitor? Bittmann S, Weissenstein A, Villalon G, Moschuring-Alieva E, Luchter E. J Clin Med Res. 2020 May;12(5):320–2. PubMed Europe PMC Scholia
  15. The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine. Rosas-Lemus M, Minasov G, Shuvalova L, Inniss NL, Kiryukhina O, Wiersum G, et al. bioRxiv. 2020 Apr 26;2020.04.17.047498. PubMed Europe PMC Scholia
  16. Chemistry and Biology of SARS-CoV-2. Dömling A, Gao L. Chem. 2020 Jun 11;6(6):1283–95. PubMed Europe PMC Scholia
  17. Crystal Structure of the SARS-CoV-2 Non-structural Protein 9, Nsp9. Littler DR, Gully BS, Colson RN, Rossjohn J. iScience. 2020 Jul 24;23(7):101258. PubMed Europe PMC Scholia
  18. Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM, et al. Antiviral Res. 2020 Sep;181:104873. PubMed Europe PMC Scholia
  19. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? Pique-Regi R, Romero R, Tarca AL, Luca F, Xu Y, Alazizi A, et al. Elife. 2020 Jul 14;9:e58716. PubMed Europe PMC Scholia
  20. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, et al. Science. 2020 Sep 4;369(6508):1249–55. PubMed Europe PMC Scholia
  21. Presence of Genetic Variants Among Young Men With Severe COVID-19. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. JAMA. 2020 Aug 18;324(7):663–73. PubMed Europe PMC Scholia
  22. Sphingosine prevents binding of SARS-CoV-2 spike to its cellular receptor ACE2. Edwards MJ, Becker KA, Gripp B, Hoffmann M, Keitsch S, Wilker B, et al. J Biol Chem. 2020 Nov 6;295(45):15174–82. PubMed Europe PMC Scholia
  23. The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2. Ogando NS, Zevenhoven-Dobbe JC, van der Meer Y, Bredenbeek PJ, Posthuma CC, Snijder EJ. J Virol. 2020 Nov 9;94(23):e01246-20. PubMed Europe PMC Scholia
  24. Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and other coronaviruses by depleting membrane cholesterol. Wang S, Li W, Hui H, Tiwari SK, Zhang Q, Croker BA, et al. EMBO J. 2020 Nov 2;39(21):e106057. PubMed Europe PMC Scholia
  25. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Clausen TM, Sandoval DR, Spliid CB, Pihl J, Perrett HR, Painter CD, et al. Cell. 2020 Nov 12;183(4):1043-1057.e15. PubMed Europe PMC Scholia
  26. Identification of novel mutations in the methyltransferase complex (Nsp10-Nsp16) of SARS-CoV-2. Azad GK. Biochem Biophys Rep. 2020 Dec;24:100833. PubMed Europe PMC Scholia
  27. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, et al. Science. 2020 Nov 13;370(6518):856–60. PubMed Europe PMC Scholia
  28. Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load. Eskier D, Suner A, Oktay Y, Karakülah G. PeerJ. 2020 Oct 12;8:e10181. PubMed Europe PMC Scholia
  29. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Wei C, Wan L, Yan Q, Wang X, Zhang J, Yang X, et al. Nat Metab. 2020 Dec;2(12):1391–400. PubMed Europe PMC Scholia