Commit cfa4b980 authored by Marek Ostaszewski's avatar Marek Ostaszewski
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README's and images updated.

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......@@ -23,11 +23,11 @@ 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)
- [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)
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model af FairdomHub (https://fairdomhub.org/models/712)
## Model at FairdomHub (https://fairdomhub.org/models/712)
......@@ -9,11 +9,11 @@ Thrombotic complications and coagulopathy frequently occur in COVID-19 [PMID: 32
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)
- [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)
- [Andreas Ruepp](https://fairdomhub.org/people/1692)
## Model af FairdomHub (https://fairdomhub.org/models/749)
## Model at FairdomHub (https://fairdomhub.org/models/749)
# SARS-CoV 2 and Electron Transport Chain
# Endoplasmic Reticulum Stress
## 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 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 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].
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].
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].
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)
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].
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
[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)
- [Cristobal Monraz-Gomez](https://fairdomhub.org/people/1582)
- [Inna Kuperstein](https://fairdomhub.org/people/1548)
- [Barbara Brauner](https://fairdomhub.org/people/1693)
## Model af FairdomHub (https://fairdomhub.org/models/719)
## Model at FairdomHub (https://fairdomhub.org/models/719)
# Endoplasmic Reticulum Stress
# SARS-CoV 2 and Electron Transport Chain
## 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 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 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].
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].
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.
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)
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.
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
[Cristobal Monraz-Gomez](https://fairdomhub.org/people/1582)
[Inna Kuperstein](https://fairdomhub.org/people/1548)
[Barbara Brauner](https://fairdomhub.org/people/1693)
- [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 af FairdomHub (https://fairdomhub.org/models/719)
## Model at FairdomHub (https://fairdomhub.org/models/719)
......@@ -18,10 +18,10 @@ Hyperinflammation is a known complication in COVID-19, causing widespread damage
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)
- [Julia Somers](https://fairdomhub.org/people/1611)
- [Emek Demir](https://fairdomhub.org/people/1589)
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model af FairdomHub (https://fairdomhub.org/models/718)
## Model at FairdomHub (https://fairdomhub.org/models/718)
......@@ -15,15 +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](https://fairdomhub.org/people/1807)
[Marius Rameil](https://fairdomhub.org/people/1802)
[Vanessa Nakonecnij](https://fairdomhub.org/people/1801)
- [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](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)
- [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 af FairdomHub (https://fairdomhub.org/models/750)
## Model at FairdomHub (https://fairdomhub.org/models/750)
......@@ -51,12 +51,12 @@ Bibliography
## Creators (alphabetically)
[Sara Aghamiri](https://fairdomhub.org/people/1659)
[Vidisha Singh](https://fairdomhub.org/people/1658)
[Anna Niarakis](https://fairdomhub.org/people/1554)
- [Sara Aghamiri](https://fairdomhub.org/people/1659)
- [Vidisha Singh](https://fairdomhub.org/people/1658)
- [Anna Niarakis](https://fairdomhub.org/people/1554)
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
- [Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model af FairdomHub (https://fairdomhub.org/models/713)
## Model at FairdomHub (https://fairdomhub.org/models/713)
# JNK pathway activation during SARS-CoV infection
## Map description
During activation JNK translocates to the nucleus to phosphorylate ATF2 and c-Jun [PMID 1749429] which in turn dimerizes with other proteins to form the AP-1 complex [PMID 15564374]. Additionally, JNK translocates to the mitochondria to phosphorylate Bcl2, promoting stress-induced apoptosis [PMID: 10567572].
Vero E6 cells infected with SARS-CoV revealed phosphorylation of JNK and its upstream kinases MAP2K4 and MAP2K7 (MKK4/MKK7) [PMID: 15916886]. Here, overexpression of SARS-CoV 3a and 7a protein increased JNK [PMID: 17141229], while SARS-CoV 3b protein induced JNK/c-Jun/AP-1 activation [PMID: 21561061], and SARS-CoV S protein induced the activation of protein kinase epsilon via JNK activation [PMID: 17267381]. Expression of SARS-CoV N protein is associated with the downregulation of prosurvival factors and apoptosis induction in COS-1 cells, possibly mediated by JNK activation [PMID: 15294014], and apoptosis induced by SARS-CoV 6 and 7a protein in Vero E6 and COS-7 cells were blocked by a JNK inhibitor [PMID: 18708124]. Therefore, JNK is a good candidate acting as a pro-apoptotic protein during SARS-CoV infection. On the other hand, a prosurvival function of JNK was suggested after Vero E6 cells were treated with JNK inhibitor that abolished persistent infection of SARS-CoV [PMID: 15916886 ], apoptosis induced by overexpression of SARS-CoV N or 6 or 7a was JNK dependent [PMID: 28933406], and activation of JNK promoted IBV-induced apoptosis [PMID: 25142592] [PMID: 29238080]. Presumably JNK might be proapoptotic during initial SARS-CoV infection but later switched to a prosurvival role in persistently infected cells [PMID: 31226023] [PMID: 28933406].
## Cross-talk with other pathways (in the map, and in general)
The MAPKs are activated in response to environmental stresses including oxidative stress, DNA damage, cancer development and viral infections. The c-Jun N-terminal kinase (JNK) belong to the MAPK pathways [PMID: 23954936]. Phosphorylation of JNK and its upstream kinases, (MAP2K4/MAP2K7 or MKK4/MKK7), was detected in SARS-CoV-infected cells [PMID: 15916886].
## Creators (alphabetically)
- [Daniela Börnigen](https://fairdomhub.org/people/1583)
## Model at FairdomHub (https://fairdomhub.org/models/735)
# COVID-19 PAMP Signaling
## Map description
The innate immune system can detect specific molecular patterns of microbes, the so-called pathogen-associated molecular patterns (PAMPs), through Pattern Recognition Receptors (PRRs). These PRRs include the big family of Toll-like receptors (TLRs) and other transmembrane but also intracellular receptors, each specified on particular PAMPs. Detection of Sars-Cov-2 is mediated through TLR3, TLR7, TLR8, RIG-I (gene: ddx58), MDA5 (gene: ifih1) and protein kinase R (PKR, gene: eif2ak2) that recognize double-stranded and single-stranded RNA either in the endosome during endocytosis of the virus particle or in the cytoplasm during the viral replication. These receptors activate different downstream pathways that can be classified into the MYD88-dependent (by TLR7 and TLR8), MYD88-independent (by TLR3), and MAVS-mediated (RIG-I and MAD5) pathways. They all lead to the activation of transcription factors such as AP1, NFKB, IRF3, and IRF7. Especially IRF3 and IRF7 are responsible for the transcription of antiviral proteins, in particular, interferon alpha and beta [1], [2].
Viral proteins that interfere with these pathways are included in the map. Sars-Cov-2 has been shown to reduce the production of type I interferons to evade the immune response [3]. The detailed mechanism is not clear yet, however, an inhibitory effect of the Sars-Cov-1 M protein (with 96.4% similarity to the Sars-Cov-2 M protein [4]) on the TRAF3:TANK:TBK1/IKKε axis and, therefore, IRF3 activation has been reported in 2009 [5]. Evidence of effects on the NFKB axis, however, is somewhat contradicting. A suppression of NFKB and COX2 transcription by the M protein has been reported as well as an NFKB activation by the N protein (with 94.3% similarity to the Sars-Cov-2 N protein [4]), both for Sars-Cov-1 [6], [7].
## Cross-talk with other pathways (in the map, and in general)
The map contains the initial recognition process of the viral particle by the innate immune system and the viral mechanisms to evade the immune response. It provides the connection between the virus entry (detecting the endosomal viral patterns), the virus replication cycle (detection cytoplasmatic viral patterns), and the effector pathways of pro-inflammatory cytokines, especially of the interferon type I class. Latter seems to play a crucial but complex role in the Covid-19 pathology. In vitro and in vivo (the latter only for Sars-Cov-1, yet) administration of Interferons (as antiviral cytokines in the immune defense) has resulted in a dose-dependent reduction of the virus titer [8], [9]. Contradictory, multiple studies have shown that ACE2, one of the main entry proteins for Sars-Cov-2 belongs to the interferon-stimulated genes (ISGs), providing arguments for a positive effect of interferons on the virus replication [10], [11]. The molecular pathways behind the Covid-19 pathology are complex and are probably the result of very specific regulatory mechanisms causing the virus’ infectiousness. Clarifying the mechanisms of how Sars-Cov-2 modulates the innate immune defense in its favor to either evade recognition or, on the other hand, stimulate the immune response to amplify its replication is crucial to understand the virus pathology.
## Creators
- [Matti Hoch](https://fairdomhub.org/people/1520)
## Contributors and reviewers
- [Shailendra Gupta](https://fairdomhub.org/people/1641)
- **Suchi Smita**
- [Julia Scheel](https://fairdomhub.org/people/1686)
## Model at FairdomHub (https://fairdomhub.org/models/735)
# Pyrimidine synthesis and deprivation pathway
## Map description
We present the pyrimidine synthesis pathway that has effects potentially both on viral DNA and RNA synthesis. Pyrimidine deprivation is a host targeted antiviral defense mechanism, which blocks the viral replication but is not exposed to viral mutation induced loss of efficacy.
Existing drugs that act on this pathway and on the enzyme DHODH (dihydroorotate dehydrogenase) in particular (like the drug teriflunomide (PMID:25342978)) but also many experimental therapeutics under development, like P1788 (PMID:31740051) or S312 and S314 (doi: https://doi.org/10.1101/2020.03.11.983056) amplify cellular response to both type-I and type II interferons. It appears that components of the DNA damage response connect the inhibition of pyrimidine biosynthesis by terifluomide (P1788 and others) to the interferon signaling pathway probably via STING induced TBK1 activation that finally amplifies interferon response to viral infection.
## Cross-talk with other pathways (in the map, and in general)
Since the pyrimidine deprivation finally leads to amplified immune response via for example IFN-gamma production, it is linked most intricately to the interferon pathways. However, other related pathways are also clearly impacted. (below)
### Downstream
Interferon pathways
HcoVs interferon induction
RTC and transcription
Virus replication cycle
## Creators
- [Zsolt Bocskei](https://fairdomhub.org/people/1657)
- [Franck Augé](https://fairdomhub.org/people/1665)
- [Anna Niarakis](https://fairdomhub.org/people/1554)
## Model at FairdomHub (https://fairdomhub.org/models/752)
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