Entry
Name
Coronavirus disease - COVID-19 - Homo sapiens (human)
Description
Coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory infection that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infects alveolar epithelial cells [mainly alveolar epithelial type 2 (AEC2) cells] through the angiotensin-converting enzyme 2 (ACE2) receptor. Upon the occupancy of ACE2 by SARS-CoV-2, the increased serum level of free Angiotensin II (Ang II) due to a reduction of ACE2-mediated degradation promotes activation of the NF-kappa B pathway via Ang II type 1 receptor (AT1R), followed by interleukin-6 (IL-6) production. SARS-CoV-2 also activates the innate immune system; macrophage stimulation triggers the overproduction of pro-inflammatory cytokines, including IL-6, and the "cytokine storm", which results in systemic inflammatory response syndrome and multiple organ failure. The combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19.
Class
Human Diseases; Infectious disease: viral
BRITE hierarchy
Pathway map
Ortholog table
Network
Element
N01307 SARS-CoV-2 S to AngII-AT1R-NOX2 signaling pathway
N01309 SARS-CoV-2 nsp3 to MDA5-IRF7/3 signaling pathway
N01310 SARS-CoV-2 nsp13 to RIG-I-IRF7/3 signaling pathway
N01312 SARS-CoV-2 S to lectin pathway of complement cascade
N01314 SARS-CoV-2 S to classical pathway of complement cascade
N01316 SARS-CoV-2 S/N to lectin pathway of coagulation cascade
N01318 SARS-CoV-2 nsp1 to translation initiation
N01319 SARS-CoV-2 nsp6 and ORF6 to RIG-I-IRF7/3 signaling pathway
N01320 SARS-CoV-2 nsp3 to RIG-I-IRF7/3 signaling pathway
N01321 SARS-CoV-2 nsp1/6/13, ORF3a/6/7b and M to IFN signaling pathway
N01322 SARS-CoV-2 nsp6/13 and ORF7a/7b to IFN signaling pathway
Disease
Drug
D10308 Baricitinib (JAN/USAN/INN)
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
4142 MAS1; MAS1 proto-oncogene, G protein-coupled receptor [KO:K04303 ]
185 AGTR1; angiotensin II receptor type 1 [KO:K04166 ]
1536 CYBB; cytochrome b-245 beta chain [KO:K21421 ] [EC:1.-.-.-]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
6347 CCL2; C-C motif chemokine ligand 2 [KO:K14624 ]
3576 CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030 ]
7132 TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158 ]
1839 HBEGF; heparin binding EGF like growth factor [KO:K08523 ]
3572 IL6ST; interleukin 6 cytokine family signal transducer [KO:K05060 ]
6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
1440 CSF3; colony stimulating factor 3 [KO:K05423 ]
1437 CSF2; colony stimulating factor 2 [KO:K05427 ]
3627 CXCL10; C-X-C motif chemokine ligand 10 [KO:K12671 ]
6192 RPS4Y1; ribosomal protein S4 Y-linked 1 [KO:K02987 ]
6191 RPS4X; ribosomal protein S4 X-linked [KO:K02987 ]
2197 FAU; FAU ubiquitin like and ribosomal protein S30 fusion [KO:K02983 ]
51187 RSL24D1; ribosomal L24 domain containing 1 [KO:K02896 ]
51121 RPL26L1; ribosomal protein L26 like 1 [KO:K02898 ]
7311 UBA52; ubiquitin A-52 residue ribosomal protein fusion product 1 [KO:K02927 ]
6166 RPL36AL; ribosomal protein L36a like [KO:K02929 ]
6175 RPLP0; ribosomal protein lateral stalk subunit P0 [KO:K02941 ]
6176 RPLP1; ribosomal protein lateral stalk subunit P1 [KO:K02942 ]
6181 RPLP2; ribosomal protein lateral stalk subunit P2 [KO:K02943 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
4615 MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729 ]
23118 TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404 ]
2353 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379 ]
3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
114548 NLRP3; NLR family pyrin domain containing 3 [KO:K12800 ]
9636 ISG15; ISG15 ubiquitin like modifier [KO:K12159 ]
57506 MAVS; mitochondrial antiviral signaling protein [KO:K12648 ]
7187 TRAF3; TNF receptor associated factor 3 [KO:K03174 ]
9641 IKBKE; inhibitor of nuclear factor kappa B kinase subunit epsilon [KO:K07211 ] [EC:2.7.11.10 ]
3661 IRF3; interferon regulatory factor 3 [KO:K05411 ]
340061 STING1; stimulator of interferon response cGAMP interactor 1 [KO:K12654 ]
3454 IFNAR1; interferon alpha and beta receptor subunit 1 [KO:K05130 ]
3455 IFNAR2; interferon alpha and beta receptor subunit 2 [KO:K05131 ]
6772 STAT1; signal transducer and activator of transcription 1 [KO:K11220 ]
6773 STAT2; signal transducer and activator of transcription 2 [KO:K11221 ]
5610 EIF2AK2; eukaryotic translation initiation factor 2 alpha kinase 2 [KO:K16195 ] [EC:2.7.11.1 ]
728 C5AR1; complement C5a receptor 1 [KO:K04010 ]
719 C3AR1; complement C3a receptor 1 [KO:K04009 ]
731 C8A; complement C8 alpha chain [KO:K03997 ]
732 C8B; complement C8 beta chain [KO:K03998 ]
733 C8G; complement C8 gamma chain [KO:K03999 ]
720 C4A; complement C4A (Rodgers blood group) [KO:K03989 ]
721 C4B; complement C4B (Chido blood group) [KO:K03989 ]
5648 MASP1; MBL associated serine protease 1 [KO:K03992 ] [EC:3.4.21.-]
2165 F13B; coagulation factor XIII B chain [KO:K03906 ]
Compound
Reference
Authors
Harrison AG, Lin T, Wang P
Title
Mechanisms of SARS-CoV-2 Transmission and Pathogenesis.
Journal
Reference
Authors
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G
Title
Immunity, endothelial injury and complement-induced coagulopathy in COVID-19.
Journal
Reference
Authors
Battagello DS, Dragunas G, Klein MO, Ayub ALP, Velloso FJ, Correa RG
Title
Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission.
Journal
Reference
Authors
Felsenstein S, Herbert JA, McNamara PS, Hedrich CM
Title
COVID-19: Immunology and treatment options.
Journal
Reference
Authors
Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M, Hirano T
Title
How COVID-19 induces cytokine storm with high mortality.
Journal
Reference
Authors
Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I
Title
COVID-19 cytokine storm: The anger of inflammation.
Journal
Reference
Authors
Farooqi F, Dhawan N, Morgan R, Dinh J, Nedd K, Yatzkan G
Title
Treatment of Severe COVID-19 with Tocilizumab Mitigates Cytokine Storm and Averts Mechanical Ventilation During Acute Respiratory Distress: A Case Report and Literature Review.
Journal
Reference
Authors
Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T, Walzer T, Francois B, Seve P
Title
Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions.
Journal
Reference
Authors
Kiselevskiy M, Shubina I, Chikileva I, Sitdikova S, Samoylenko I, Anisimova N, Kirgizov K, Suleimanova A, Gorbunova T, Varfolomeeva S
Title
Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence?
Journal
Reference
Authors
Curran CS, Rivera DR, Kopp JB
Title
COVID-19 Usurps Host Regulatory Networks.
Journal
Reference
Authors
Quan C, Li C, Ma H, Li Y, Zhang H
Title
Immunopathogenesis of Coronavirus-Induced Acute Respiratory Distress Syndrome (ARDS): Potential Infection-Associated Hemophagocytic Lymphohistiocytosis.
Journal
Reference
Authors
Ahmed-Hassan H, Sisson B, Shukla RK, Wijewantha Y, Funderburg NT, Li Z, Hayes D Jr, Demberg T, Liyanage NPM
Title
Innate Immune Responses to Highly Pathogenic Coronaviruses and Other Significant Respiratory Viral Infections.
Journal
Reference
Authors
Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP
Title
The trinity of COVID-19: immunity, inflammation and intervention.
Journal
Reference
Authors
Xia H, Cao Z, Xie X, Zhang X, Chen JY, Wang H, Menachery VD, Rajsbaum R, Shi PY
Title
Evasion of Type I Interferon by SARS-CoV-2.
Journal
Reference
Authors
Hartenian E, Nandakumar D, Lari A, Ly M, Tucker JM, Glaunsinger BA
Title
The molecular virology of coronaviruses.
Journal
Reference
Authors
Amor S, Fernandez Blanco L, Baker D
Title
Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage.
Journal
Reference
Authors
Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C
Title
Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2.
Journal
Reference
Authors
Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, Nemati M
Title
Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions.
Journal
Reference
Authors
Merad M, Martin JC
Title
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.
Journal
Reference
Authors
South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA
Title
Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic.
Journal
Reference
Authors
Furuhashi M, Moniwa N, Takizawa H, Ura N, Shimamoto K
Title
Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19.
Journal
Reference
Authors
Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V
Title
COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?
Journal
Reference
Authors
Kielian M
Title
Enhancing host cell infection by SARS-CoV-2.
Journal
Reference
Authors
Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, Lambris JD
Title
Complement as a target in COVID-19?
Journal
Reference
Authors
Noris M, Benigni A, Remuzzi G
Title
The case of complement activation in COVID-19 multiorgan impact.
Journal
Reference
Authors
Polycarpou A, Howard M, Farrar CA, Greenlaw R, Fanelli G, Wallis R, Klavinskis LS, Sacks S
Title
Rationale for targeting complement in COVID-19.
Journal
Reference
Authors
Teuwen LA, Geldhof V, Pasut A, Carmeliet P
Title
COVID-19: the vasculature unleashed.
Journal
Reference
Authors
Jodele S, Kohl J
Title
Tackling COVID-19 infection through complement-targeted immunotherapy.
Journal
Reference
Authors
Chauhan AJ, Wiffen LJ, Brown TP
Title
COVID-19: A collision of complement, coagulation and inflammatory pathways.
Journal
Reference
Authors
Colling ME, Kanthi Y
Title
COVID-19-associated coagulopathy: An exploration of mechanisms.
Journal
Reference
Authors
McFadyen JD, Stevens H, Peter K
Title
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.
Journal
Reference
Authors
Shi M, Wang L, Fontana P, Vora S, Zhang Y, Fu TM, Lieberman J, Wu H
Title
SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism.
Journal
Reference
Authors
Paniri A, Akhavan-Niaki H
Title
Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation.
Journal
Reference
Authors
Omarjee L, Janin A, Perrot F, Laviolle B, Meilhac O, Mahe G
Title
Targeting T-cell senescence and cytokine storm with rapamycin to prevent severe progression in COVID-19.
Journal
Reference
Authors
Zhang S, Li L, Shen A, Chen Y, Qi Z
Title
Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia.
Journal
Related pathway
hsa04270 Vascular smooth muscle contraction
hsa04610 Complement and coagulation cascades
hsa04613 Neutrophil extracellular trap formation
hsa04620 Toll-like receptor signaling pathway
hsa04621 NOD-like receptor signaling pathway
hsa04622 RIG-I-like receptor signaling pathway
hsa04650 Natural killer cell mediated cytotoxicity
hsa04666 Fc gamma R-mediated phagocytosis
hsa04670 Leukocyte transendothelial migration
KO pathway
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