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# Innate Immunity and Type 1 Interferon pathway
## Map description
### Abbreviations:
PMPs- pathogen-associated molecular patterns,
PRRs-pattern recognition receptors,
IRF3-interferon regulatory factor 3,
NF-κB- nuclear factor kappa-light-chain-enhancer of activated B cells,
AP-1 activator protein 1,
IFN-I type I interferons,
IFNAR IFN-α/β receptor,
ISGs interferon-stimulated genes,
JAK1- Janus kinase 1,
STAT- signal transducer and activator of transcription 1,
TLR Toll-like receptor,
RLRs RIG-I-like receptors,
Innate immunity plays an important role in the detection and restriction of pathogens and also activation of the adaptive immune response. Effective activation of innate immunity relies on the:
Recognition pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs)
PRRs recruit adaptor proteins, which initiate complicated signalling pathways involving multiple kinases.
Activation of critical transcription factors including interferon regulatory factor 3 (IRF3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and activator protein 1 (AP-1).
These factors promote the production of type I interferons (IFN-I), which are released and act on neighbouring cells by binding to IFN-α/β receptor (IFNAR)
The antiviral activity of IFN-I is mediated by the induction of numerous interferon-stimulated genes (ISGs), which antagonize viral replication by various mechanisms.
### How they are related to the COVID:
While mild HCoVs typically induced a high level of IFN-I production (Dendritic Cells, MeSH ID: D003713) [ref 1] [PMID: 22553325]. SARS-COVID proteins were shown to utilize mechanisms to suppress the activation of host innate immune response. Several structural proteins (M and N), nonstructural proteins (nsp1 and nsp3), and accessory proteins of SARS-COVID were identified as interferon antagonists [refs 2–5] [PMID: 31226023, PMID: 32201497, PMID: 28933406, PMID: 24995382].
### What are the key molecular mechanisms:
1. Binding the IFN1 to IFNAR triggers the JAK1/STAT pathways which fall into the activation of the immune response 2 [PMID: 31226023].
2. PAMPs trigger the activation of TLR7 (TLRs) and RIG-I-like receptors (RLRs) [ref 4] [PMID: 28933406] which recruit adaptor proteins, initiating signalling pathways involving multiple kinases. This cascade leads to the activation of crucial transcription factors such as IRF3, NF-κB, and AP-1. These factors promote the production of IFN-I, which are released and act on neighbouring cells by binding to the IFN-α/β receptor (IFNAR) [ref 4] [PMID: 28933406].
3. The antiviral activity of IFN-I is mediated by the induction of ISGs. Also, cytokines and chemokines are induced to activate an inflammatory response, which is also sometimes responsible for extensive tissue damage and other immunopathies associated with Human-COVID infection [ref 6] [PMID: 19430490].
## Cross-talk with other pathways (in the map, and in general)
Since PAMPs are the trigger for PRRs, this map may have cross-talk with “PAMP signalling”, “HCoVs Ifn induction (WP4880) and HCoVs Type I Ifn signaling (WP4868)”, and “Orf3a interactions” that all of them share TLR7 (TLRs).
All of the pathways mentioned plus “Pyrimidine deprivation” can have cross-talk with our map by IFN (IFNB1, IFNA1) which is related to IFN pathways.
Downstream of our map (immune response phenotype) and (inflammation phenotype) may have cross-talk with “Pyrimidine deprivation” by its induction_of_cellular_immune_response_phenotype and also “HCoVs Ifn induction (WP4880) and HCoVs Type I Ifn signaling (WP4868)”, “JNK pathway” by Innate_immunity_phenotype. With “SARS-CoV-2 NLRP3 Inflammasome (WP4876)” by NLRP3_inflammasome_complex
Bibliography
1. Mesel-Lemoine, M. et al. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes. J. Virol. 86, 7577–7587 (2012).
2. Fung, T. S. & Liu, D. X. Human Coronavirus: Host-Pathogen Interaction. Annu. Rev. Microbiol. 73, 529–557 (2019).
3. Fung, T. S. & Liu, D. X. Post-translational modifications of coronavirus proteins: roles and function. Future Virol. 13, 405–430 (2018).
4. Lim, Y. X., Ng, Y. L., Tam, J. P. & Liu, D. X. Human Coronaviruses: A Review of Virus-Host Interactions. Diseases 4, (2016).
5. Liu, D. X., Fung, T. S., Chong, K. K.-L., Shukla, A. & Hilgenfeld, R. Accessory proteins of SARS-CoV and other coronaviruses. Antiviral Res. 109, 97–109 (2014).
6. Perlman, S. & Netland, J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat. Rev. Microbiol. 7, 439–450 (2009).
## Creators (alphabetically)
- [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)
## 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)
# SARS-CoV-2 mechanisms of transcription and RTC
## Map description
The map shows a key mechanism of the viral life cycle, the viral gene expression of proteins involved in genome replication and the production of the viral proteins. The initial step in this process is the creation of the viral replication transcription complex (RTC). After expression of pp1a and pp1ab [PMID 18798692] the two proteins are split into 16 nonstructural proteins (Nsps) [PMID 16928755] that form the RTC [PMID 24348241, PMID 16228002]. Nsp3, Nsp4 and Nsp6 induce the formation of double membrane vesicles (DMVs) that are built from ER membranes [PMID23943763]. Inside the DMVs the genomic RNA (gRNA) gets replicated, new RTCs are built and subgenomic RNAs (sgRNAs) are transcribed [PMID 18451981]. The sgRNAs are translated into viral accessory and structural proteins.
## Cross-talk with other pathways (in the map, and in general)
The transcription and formation of the RTC is a central process in the viral replication cycle. After the nucleocapsid enters the host cell cytoplasm the Sars-CoV-2 RNA is released and the RTC is built. After the transcription of the genomic RNA (gRNA) as well as the subgenomic RNA (sgRNA) the viral proteins are translated. New nucleocapsids are packed, enveloped by a membrane, and released from the host cell.
Using the ER membrane as transcription and replication network is a common strategy in single stranded RNA (ssRNA) viruses that is thought to shield the virus from the host immune system [PMID 18798692], [PMID 18451981]. The two Toll-like receptors TLR7 and TLR8 recognize ssRNA and induce an innate immune signaling cascade [PMID 22258243] (PAMP signaling pathway). The Nsps interact with multiple other pathways: Nsp9 interactions, Nsp14 and metabolism, Nsp4 and Nsp6 interactions and the Interferon1 pathway (Nsp3).
## Creators
- [Hanna Borlinghaus](https://fairdomhub.org/people/1597)
- [Tobias Czauderna](https://fairdomhub.org/people/1559)
- [Falk Schreiber](https://fairdomhub.org/people/1533)
## Model at FairdomHub (https://fairdomhub.org/models/704)
# Renin-angiotensin system
## Map description
SARS-CoV-2 uses ACE2 (angiotensin-converting enzyme 2) as receptor to enter host cells. ACE2 is a regulator of the renin-angiotensin system (RAS) and is widely expressed in the organs affected in COVID-19 patients like lungs, kidneys, cardiovascular system, gut, and central nervous system.
An important function of ACE2 is the conversion of angiotensin II (AngII) to angiotensin 1-7 (Ang1-7). These two angiotensins trigger counter-regulatory arms of the RAS. The signaling via AngII and its receptor AGTR1 induces deleterious effects (e.g. vasoconstriction, inflammation, thrombosis), while the signaling via Ang1-7 and its receptor MAS1 attenuates these effects. In SARS-CoV2 patients AngII levels are elevated, so that the balance is shifted towards the harmful signaling via AngII/AGTR1. RAS, which includes not only AngII, Ang1-7, AGTR1 and MAS1 but more angiotensin forms and receptors, is tightly regulated and it is influenced by factors that are known to increase the risk to develop severe forms of COVID-19, like hypertension, male sex, or aging.
RAS-inhibiting drugs, ACE inhibitors (ACEi) and Angiotensin II type 1 receptor blockers (ARB), are commonly used in the treatment of hypertension and chronic kidney disease. The role of the RAS in the pathogenesis of COVID-19 and the effects of ACEis and ARBs on the risk of COVID-19 infection and disease progression are currently under investigation [PMID 31427727; PMID 32264791; PMID 32336612].
Similarly, the role of activated vitamin D (Calcitriol) as a negative regulator of renin transcription is currently being studied as a potential factor that may influence the severity of COVID-19 [PMID 32252338]. Further known small molecule compounds and drugs that influence the activity of key enzymes and receptors in the RAS have been annotated in the map.
## Cross-talk with other pathways (in the map, and in general)
Describe the role of your pathway/diagram in a bigger context. Provide a short list of upstream and downstream pathways, both in the map and in general, that interact with the mechanisms you have drawn. You can check the current content of the COVID-19 Disease Map here: [https://covid19map.elixir-luxembourg.org](https://covid19map.elixir-luxembourg.org).
The pathway is interlinked with the “Virus replication cycle” map via ACE2 as the main receptor for viral entry into host cells, and viral replication can be regarded as a downstream pathway after viral entry. Moreover, the pathway has generic downstream mechanisms (not within the map), which include inflammation, oxidative stress, vasoconstriction, fibrosis, pulmonary edema, and coagulation/thrombosis (downstream of AGTR1, counter-acted by MAS1 signaling), decreased neurodegeneration and improved cognition (downstream of LNPEP).
## Creators
- [Enrico Glaab](https://fairdomhub.org/people/1674)
- [Gisela Fobo](https://fairdomhub.org/people/1695)
- [Corinna Montrone](https://fairdomhub.org/people/1694)
## Contributors and reviewers
[Andreas Ruepp](https://fairdomhub.org/people/1692)
[Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/709)
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