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# Apoptosis
## Map description
Innate cell death machinery also called Apoptosis or programmed cell death is one of the many host cellular responses triggered by virus-host interaction upon viral infection. The induction of apoptosis is considered to be a host defence response as the early death of the virus-infected cells could prevent viral replication. Many viruses have developed a countermeasure(s) that effectively blocks or delays cell death by expressing anti-apoptotic proteins to maximize the production of viral progeny (12441076). Apoptosis induction at the end of the viral replication cycle might assist in viral dissemination while attenuating an inflammatory response.
Apoptosis can be activated through both intrinsic and extrinsic pathways in the cell.
Intrinsic pathway includes proteins of the BCL2 family which could be both pro-apoptotic and anti-apoptotic. Pro-apoptotic proteins like BAX and BAK1 are channel-forming proteins that increase the mitochondrial outer membrane permeability (MOMP) while Bcl2, Bcl-xL, and Mcl-1 are anti-apoptotic factors that inhibit this process. Extrinsic pathways include the binding of the death ligands [such as FasL and tumour necrosis factor-α (TNF-α)] to the cell surface death receptors (such as Fas and TNF receptor 1). This initiates death-inducing signalling complex and activation of caspase 8, which either directly activates effector caspases or engages in cross-talk with the intrinsic pathway by activating the BH3-only protein Bid. Bid protein activates BAX proteins in the mitochondria which eventually releases Cytochrome C in the cytoplasm where it interacts with APAF1 protein and procaspase 9 resulting in the formation of Apoptosome complex (31226023).
Apoptosis induced by HCoV infection in different cell/tissue types:
HCoV-OC43 induced apoptosis in neuronal cells (22013052)
SARS-CoV infected lung, spleen, and thyroid tissues (19109397)
MERS-CoV induced apoptosis in primary T lymphocytes (26203058)
HCoV-229E infection also causes massive cell death in dendritic cells (22553325)
SARS-CoV-2 (Covid-19) induces lymphocyte apoptosis via enhancing Fas signaling (https://doi.org/10.1101/2020.03.27.20045427)
## Cross-talk with other pathways (in the map, and in general)
Apoptosis is regulated by Upstream Pathways FASL and TNF and the downstream pathways include AKT and MAPKs. AKT and MAPKs operate individually in the regulation of Apoptosis and are not activated by the upstream TNF and FASL pathway.
Cross talks with other pathways in the COVID-19 disease map:
ER stress via BCL2 and BAX protein
JNK pathway via BCL2 protein
HCoVs ER stress (WP4869) via MAPKs (however, Apoptosis pathway is regulated by MAPK14 while in HCoVs ER stress (WP4869) pathway, Apoptosis is regulated by a complex of MAPKs (MAPK8,9,10)
## Creators
- [Vidisha Singh](https://fairdomhub.org/people/1658)
- [Anna Niarakis](https://fairdomhub.org/people/1554)
- [Sara Ahgamiri](https://fairdomhub.org/people/1659)
## Contributors and reviewers
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/712)
# SARS-CoV-2 coagulation pathway
## Map description
Thrombotic complications and coagulopathy frequently occur in COVID-19 [PMID: 32552865]. Recently, a high incidence of venous thromboembolism was found by consecutive autopsy findings noting frequent deep vein thrombosis in 7 of 12 COVID-19 cases; pulmonary embolism was the direct cause of death in 4 patients (33%) [PMID:32374815]. Characteristics of COVID-19-associated coagulopathy are increased D-dimer and fibrinogen levels but initially minimal abnormalities in prothrombin time and platelet count. Moreover, hyperinflammation also induces endothelial dysfunction leading to microvascular thrombosis with further organ damage (PMID:32348783). There are multiple connections between coagulopathy and pathways that were found to be involved in SARS-CoV-2 infections. 1.) The increased level of Angiotensin II after virus infection, which indicates the renin-angiotensin system imbalance, mediates activation of different components of the coagulation cascade that leads to microvascular thrombosis (PMID:24495185). 2.) The COVID-19 non‐survivors revealed significantly higher D‐dimer and fibrin degradation product levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (PMID:32073213). 3.) The crosstalk of the SARS-CoV-2 virus with the kallikrein-kinin system and the complement cascade play a role in the development of microvascular thrombosis. 4.) SARS-CoV-2 spike glycoprotein was shown to co-localize with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 Covid-19 cases examined and the C4d-deposits found in COVID-19 patients may be correlated with septal capillary necrosis (PMID:32299776). 5.) Inflammatory biomarkers (IL1beta, IL-6, IL8, IL-10), coagulation factors (C-reactive protein, Factor VIII, VWF, protein C) and complementation components (C4d, C5b-9) were highly upregulated in patients with severe and fatal disease (PMID:32504360, PMID:32286245).
## Cross-talk with other pathways (in the map, and in general)
Our pathway model shows how the proteins with altered expression level can be integrated in a tightly interconnected network. This network intends to identify potential regulatory mechanisms between of five thrombosis related pathways such as coagulation cascade, renin-angiotensin system, complement component cascade, kallikrein-kinin system and hyperinflammation for COVID-19 patients with severe immunothrombosis. SARS-CoV-2 infection coagulation pathway is interlinked with the “SPIKE-ACE2-RAS pathway” map via ACE2 and pro-thrombotic function of Angiotensin II. SARS-CoV-2 infection triggers hyperinflammation that leads detrimental hypercoagulability and immunothrombosis. Therefore, this pathway also be linked to “SARS-CoV-2 NRLP3 Inflammasome (WP4876)” via “cytokine storm” and “PAMP signaling” via “transcription of pro-inflammatory factors”.
## Creators
- [Goar Frishman](https://fairdomhub.org/people/1696)
- [Gisela Fobo](https://fairdomhub.org/people/1695)
- [Corinna Montrone](https://fairdomhub.org/people/1694)
## Contributors and reviewers
- [Andreas Ruepp](https://fairdomhub.org/people/1692)
## Model at FairdomHub (https://fairdomhub.org/models/749)
# Endoplasmic Reticulum Stress
## Map description
The endoplasmic reticulum (ER), is a vast organelle with many functions for cell homeostasis, such as Ca2+ storage, synthesis and folding of proteins as well as carbohydrate and lipid metabolism. Many conditions, such as oxidative stress, altered Ca2+ homeostasis, fails on protein folding can cause the accumulation of unfolded or misfolded proteins in the ER, leading to the stress of this organelle. The ER has many pathways to resolve this stress, however, when it fails to restore its function can trigger cell apoptosis [PMID 25387057], [PMID 25656104].
The expression of some HCoV proteins during infection, specially the S glycoprotein, might induce the activation of the ER stress in the host’s cells [PMID 22915798]. The unfolded protein response pathways are key to assure the ER homeostasis, these pathways are activated by the protein kinase RNA-activated (PKR)-like ER protein kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) [PMID 31226023]. During SARS-Cov infection, it has been proved the activation of the PERK [PMID 19109397], IRE1 [PMID 22028656] and, in a less studied and indirect manner, ATF6 pathways [PMID 19304306].
This map depicts the activation of the main UPR actors (ATF6. IRE1 and PERK) upon unfolded protein accumulation, and their role of this response to Ca2+ release into the cytoplasm as well as the activation of molecules that can lead to apoptosis and cell death.
## Cross-talk with other pathways (in the map, and in general)
This map can be linked to the ER quality control map as an upstream pathway and as downstream pathway the apoptosis map and also calcium homeostasis.
## Creators
- [Cristobal Monraz-Gomez](https://fairdomhub.org/people/1582)
- [Inna Kuperstein](https://fairdomhub.org/people/1548)
- [Barbara Brauner](https://fairdomhub.org/people/1693)
## Model at FairdomHub (https://fairdomhub.org/models/719)
# SARS-CoV 2 and Electron Transport Chain
## Map description
The primary functions of mitochondria are the production of ATP, the energy currency of the cell and to regulate cellular metabolism [DOI 10.1186/s12915-015-0201-x]. It is affected by SARS-CoV-2 on several levels [DOI 10.1101/2020.03.22.002386]. The mammalian mitochondrial electron transport chain (ETC) consists of in the inner membrane embedded complexes I-IV, and the electron transporters cytochrome c and ubiquinone [DOI 10.3892/ijmm.2019.4188]. the oxidative phosphorylation system (OXPHOS) complex comprise the ETC and complex V. Each complex consists of catalytic activity performing core proteins and a large number of subunits supporting assembly, regulation and stability. Complex assembly is further supported by OXPHOS factors which are encoded by both mitochondrial and nuclear DNA [PMID: 30030361].
The ETC generates a proton gradient across the mitochondrial inner membrane, which is used by complex V to produce ATP. Some electrons are transferred to O2, causing the generation of reactive oxygen species (ROS) [DOI 10.3892/ijmm.2019.4188]. Complex I is also involved in superoxide production via paraquate [PMID: 18039652].
SARS-CoV-2 open reading frame 9c (Orf9c) interacts with the complex I subunits NDUFB9 and NDUFA1 and the OXPHOS factors ACAD9 and ECSIT, while non-structural protein (Nsp) 7 interacts with NDUFAF7 [DOI 10.1101/2020.03.22.002386].
Mitochondrial ribonucleoprotein biogenesis is inhibited by Nsp8’s interaction with the mitochondrial ribosomal proteins MRPS5, MRPS27, MRPS2, and MRPS25. tRNA methyltransferase 1 (TRMT1), which modulates mitochondrial tRNA [PMID: 28752201] interacts with nsp5, possibly confining TRMT1 to the mitochondrion [DOI 10.1101/2020.03.22.002386].
Mitochondrial protein import is inhibited by both Nsp4 and Orf9b. The translocase of the inner membrane (TIM) complexes and translocase of the outer membrane (TOM) complex support the transport of protein precursors into the mitochondrial matrix and the mitochondrial membrane [10.1146/annurev.cellbio.13.1.25]. While Nsp4 interacts with TIM subunits TIM9 and TIM10,
Orf9b interacts with mitochondrial import receptor Tom70 [DOI: 10.1101/2020.03.22.002386v3], which is not only involved in mitochondrial protein transport but also in IRF-3 activation [DOI: 10.1038/cr.2010.103].
## Cross-talk with other pathways (in the map, and in general)
The map contains the ETC, complex V including OXPHOS factors, mitochondrial ROS production, mitochondrial transmembrane transport (TIM and TOM complexes) of proteins, and mitochondrial DNA transcription and translation. Not included are Apoptosis, Necrosis, and a detailed network of the citric acid cycle (TCA) with its connections to glycolysis and fatty acid biosynthesis.
It has been shown that within the mitochondrion, SARS-CoV-2 subunits predominantly interact with complex I subunits [Doi 10.1101/2020.03.22.002386], which may interrupt the mitochondrial membrane potential, mitochondrial reactive oxygen species (ROS) production, and the electron transport chain [PMID: 18039652, PMID: 26770107]. Complex I inhibition is further associated with dopaminergic cell death [PMID: 2154550].
ROS play an important role in cell proliferation, cell differentiation, and adaptation to hypoxia via redox sensitive pathways. Incorrect ROS production can lead to irreversible mitochondrial oxidative damage, cell damage, and cell death [Doi 10.1016/j.pneurobio.2011.01.007].
Considering that out of the 1500 different proteins within the mitochondrion 99% are encoded by the nuclear genome and transferred into the mitochondrion via TOM and TIM [PMID: 30405116], a dysfunction of said complexes leads to further inhibition of complex I and mitochondrial function in general. As mitochondria are present in all mammalian cells, these effects can present anywhere within the system, in fact mitochondrial dysfunction has been associated with excessive fatigue and various chronic diseases [PMID: 26770107].
## Creators
- [Julia Scheel](https://fairdomhub.org/people/1686)
## Contributors and reviewers
- [Shailendra Gupta](https://fairdomhub.org/people/1641)
- [Matti Hoch](https://fairdomhub.org/people/1520)
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/719)
# Immune Modulation by Heme and Tryptophan Catabolism
## Map description
Heme catabolism begins with heme oxygenase 1 (HO-1), the enzyme responsible for cleaving heme into biliverdin (BV), carbon monoxide (CO), and ferrous iron (Fe2+) [PMID: 26166253, PMID: 31827672, PMID: 30013453, DOI: 10.3389/fphar.2019.00825]. BV is converted to Bilirubin (BR), and Fe2+ is sequestered and converted to ferric iron (Fe3+) by ferritin [DOI: 10.3389/fphar.2019.00825]. Accumulation of free iron can trigger ferroptosis, a form of programmed cell death [PMID: 30692038]. HO-1 expression is regulated by NRF-2. Under stressful conditions, NRF-2 is stabilized and translocates to the nucleus to activate an arsenal of cytoprotective genes [PMID: 20173742, PMID: 30692038].
HO-1 is a recognized immuno-protective agent in many disease types [PMID: 15451051, DOI: 10.3389/fphar.2019.00825]. Polymorphisms in (GT)n repeat length at the HO-1 promoter affect HO-1 expression, and are associated with comorbidities frequently observed in severe cases of COVID-19, including diabetes and various cardiovascular diseases [DOI: 10.1016/j.freeradbiomed.2004.07.008, PMID: 27473828, PMID: 20682519]. These polymorphisms have even been linked to predisposition for ARDS, a leading cause of death in COVID-19 patients [PMID: 19526221].
Indoleamine 2,3 dioxygenase (IDO-1) is the rate limiting enzyme in the conversion of tryptophan to kynurenines, which modulate the immune response. L-kynurenine is a substrate for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor that promotes the generation of regulatory T cells to calm hyperinflammation [PMID: 249307]. Tryptophan scarcity also inhibits T cell proliferation. Downstream kynurenines 3-hydroxyanthralinic acid (3-HA) and quinolinic acid induce apoptosis in a subset of thymocytes in a manner comparable to the effect of dexamethasone, a steroid which has recently shown efficacy in improving survival in COVID-19 patients requiring oxygen or mechanical ventilation [PMID: 16709834, PMID: 12232796 , RECOVERY Trial Press Release]. Interestingly, a preprint by Thomas et.al. reported significantly higher kynurenine pathway activity based on serum metabolomics from COVID-19 positive patients relative to healthy controls, highlighting this pathway’s relevance to the disease [DOI: 10.1101/2020.05.14.20102491].
Expression of both IDO-1 and HO-1, as well as inducible nitric oxide synthase (iNOS) can be induced by the inflammatory cytokine IFN-g. IDO-1 expression is inhibited, whereas HO-1 expression and activity are enhanced, by cytotoxic nitric oxide (NO) produced by iNOS [DOI: 10.1016/j.bbrc.2004.06.061, PMID: 7514170]. 3-HA produced by IDO-1 inhibits NO production by enhancing expression of HO-1, however the mechanism by which this inhibits iNOS is not fully elucidated. One theory is that CO produced by HO-1 inhibits the transcription factor NF-KB, which is essential to iNOS expression [DOI: 10.1016/j.bbrc.2004.06.061].
## Cross-talk with other pathways (in the map, and in general)
Hyperinflammation is a known complication in COVID-19, causing widespread damage, organ failure and death. An article from Quartuccio et. al. echoes the importance of targeting inflammation to prevent the onset of the catastrophic cytokine storm and ARDS [PMID: 32321634]. The immunomodulatory properties of heme and tryptophan catabolism present an opportunity to target the hyperactive immune environment. HO-1 can be pharmacologically induced, making this an attractive prospect for further study. Multiple animal models, including non-human primates, have demonstrated anti-inflammatory properties of CO produced by HO-1, leading researchers to explore the potential of inhaled or CORM-administered CO as a therapeutic [DOI: 10.3390/ma12101643]. A phase I clinical trial of low dose carbon monoxide in patients with sepsis-induced ARDS confirmed the safety and feasibility of this therapy in humans, though further investigation is still needed [PMID: 31137526, PMID: 30518685, DOI: 10.1152/ajplung.00366.2009, DOI: 10.4049/jimmunol.1202969]. HO-1 can also be induced by Panhematin (hemin), or Dimethyl fumarate (DMF) [PMID: 32132672, DOI: 10.3389/fphar.2019.00825, DOI: 10.1155/2018/9413876].
This pathway may overlap with the following existing disease map pathways: Orf3a Interactions, the Impact of Nsp14 on Metabolism, the Apoptosis pathway, the ER Stress pathway, and the Interferon pathway. An interaction between HO-1 and Orf3a were identified in the SARS-CoV-2 host protein interactome published by Gordon et. al., however the nature of this interaction is unknown [PMID: 32353859]. Nicotinamide synthesis, which is represented in the Nsp14 pathway, occurs downstream of the tryptophan metabolite 2-amino-3-carboxymuconate semialdehyde. The ER stress pathway may also be relevant to heme and tryptophan catabolism, as HO-1 was shown to modulate proapoptotic Bcl-2 and ER stress pathways in a mouse model of sepsis-induced ALI [DOI: 10.1155/2018/9413876]. There may also be overlap with the interferon pathway, however the heme/tryptophan pathway is more involved with interferon-gamma as opposed to interferons -alpha and -beta. Other general pathways that would help to contextualize this pathway are high level curation of the innate immune response to SARS-CoV-2, initiation of the cytokine storm, detailed iron homeostasis, and T-cell differentiation.
## Creators
- [Julia Somers](https://fairdomhub.org/people/1611)
- [Emek Demir](https://fairdomhub.org/people/1589)
## Contributors and reviewers
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/718)
......@@ -15,13 +15,15 @@ IFNL may be the main IFN produced in lung cells during viral infection based on
- HCoVs IFN induction (WP4880)
## Creators (alphabetically)
Marta Conti
Marius Rameil
Vanessa Nakonecnij
- [Marta Conti](https://fairdomhub.org/people/1807)
- [Marius Rameil](https://fairdomhub.org/people/1802)
- [Vanessa Nakonecnij](https://fairdomhub.org/people/1801)
## Contributors and reviewers
Marta Conti
Marius Rameil
Vanessa Nakonecnij
Jakob Vanhoefer
Jan Hasenauer
- [Marta Conti](https://fairdomhub.org/people/1807)
- [Marius Rameil](https://fairdomhub.org/people/1802)
- [Vanessa Nakonecnij](https://fairdomhub.org/people/1801)
- [Jakob Vanhoefer](https://fairdomhub.org/people/1800)
- [Jan Hasenauer](https://fairdomhub.org/people/842)
## Model at FairdomHub (https://fairdomhub.org/models/750)
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