MecCog

Schema Name	TLR9 Schema for Crohn's disease
Accession	MS020700040.2
Gene(s)	TLR9
Schema Caption	The role of variants in TLR9 locus in Crohn's disease
Schema Description	Toll-like receptors are pattern recognition receptors and recognize invading pathogens and endogenous molecules in the cell, part of the innate immune system. TLR9 is a DNA sensing receptor, recognizes the un-methylated CpG-DNA of bacteria or virus. Unlike TLR2 or TLR4, which are located on the cell surface, TLR9 localizes in the intracellular compartments, endosome. It is expressed in intestinal epithelial cells. This schema is addressing the role of variants in TLR9 in Crohn's disease, where we can see that both gain of function variant and loss of function variant of the protein are related to increasing in disease risk. The GWAS marker found from a small German study (pmid: 15236225) is related to the increase in expression of the protein, leading to the higher abundance of the protein and thereby towards increase in inflammation, relevant for Crohn's disease phenotype. On the other hand, Tlr9 deficient mice (pmid: 22893852), which has zero protein abundance leads to delayed wound healing, another characteristic feature of Crohn's disease. In the present schema we addressed how these two types of variants are contributing towards increase in Crohn's disease risk.
Author(s)	Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s)	Lipika R. Pal, John Moult
Last Modified	Fri Aug 10 2018 15:23:46 GMT-0400 (Eastern Daylight Time)

Sub-state Perturbation (SSP) Annotations

Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs5743836 in TLR9
Confidence Score: 3
Comment: TLR9 polymorphisms are associated with Crohn's disease. This GWAS marker is based on a small German study which is claiming the association with Crohn's disease. There is another larger study on Danish population, where they found TLR9 marker (rs187084) to be associated with IBD, but no statistical significant association with CD. Because of these conflicting information, we are using medium confidence color here. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:15236225, PMID:22132241
Against Evidence: PMID:24971461

Component ID: SSP2
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: NM_017442: c.-1237T>C
Confidence Score: 3
Comment: We are not sure whether for Crohn's patient, this altered mRNA abundance is applicable or not - so medium confidence.
For Evidence: PMID:22132241
Against Evidence:

Component ID: SSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: TLR9
Confidence Score: 5
Comment: More TLR9 protein will be available - usual process.
For Evidence:
Against Evidence:

Component ID: SSP4
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: Ligand bounded TLR9
Confidence Score: 5
Comment: There will be more ligand bounded TLR9
For Evidence: PMID:20490286
Against Evidence:

Component ID: SSP5
Stage: Protein
SSP Class: Protein Conformation
Other SSP Class:
Modifier: Altered
Ontology: MESH
SSP Instance: Activated TLR9
Confidence Score: 5
Comment: Activated TLR9 is formed due to ligand binding, transport and proteolytic cleavage.
For Evidence: PMID:20490286
Against Evidence:

Component ID: SSP6
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: TLR9-MyD88, IRAK1, TRAF6
Confidence Score: 5
Comment: Active TLR9 recruits adaptor protein MyD88, followed by further recruitment of IRAK1/TRAF6 – initiating a signaling cascade. Two major pathways get activated due to this signaling.
For Evidence: PMID:20490286
Against Evidence:

Component ID: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Chemokines, Cytokines
Confidence Score: 5
Comment: Activated pathways lead to increased abundance of pro-inflammatory Chemokines and Cytokines or adhesion molecules.
For Evidence: PMID:20490286
Against Evidence:

Component ID: SSP10
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: Increased inflammation and delayed wound healing are two main characteristics of Crohn's patients and TLR9 contributes to increased disease risk by both the processes.
For Evidence:
Against Evidence:

Component ID: SSP8
Stage: DNA
SSP Class: Other
Other SSP Class: Mouse KnockOut
Modifier: NA
Ontology:
SSP Instance: Tlr9 deficient mice
Confidence Score: 5
Comment: TLR9 deficient mouse is susceptiple to dextran-sulfate sodium (DSS) induced intestinal damage.
For Evidence: PMID:22893852
Against Evidence:

Component ID: SSP9
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: VEGF, HES1
Confidence Score: 3
Comment: Reduced expression of VEGF and HES1 are observed for Tlr9 deficient mouse without any clue for the mechansim. There is no human study available corresponding to this observation, so we used medium confidence color here.
For Evidence: PMID:22893852, PMID:20946144
Against Evidence:

Biomarker(s) Annotations

Mechanism Module (MM) Annotations

Component ID: MM1
Mechanism Class Name: Transcription
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased Transcription
Confidence Score: 3
Comment: For rs5743836 variant, the minor allele shows upregulation of mRNA expression [pmid: 22132241] and also from GTEX portal data (accessed on 16 Dec 2017), we can see this upregulation in expression for TLR9. There is some evidence that in Ulcerative Colitis patients, TLR9 mRNA expression is increased [pmid: 25780451], however there is no change in expression for CD patients [Table 3, pmid: 29155256]. Because of this ambiguity, we gave a medium confidence code (orange color) in this part of the chain.
For Evidence: PMID:22132241, PMID:25780451
Against Evidence: PMID:29155256

Component ID: MM2
Mechanism Class Name: Translation Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased Translation
Confidence Score: 5
Comment: Usual process of getting increased translation from increased mRNA abundance
For Evidence:
Against Evidence:

Component ID: MM3
Mechanism Class Name: Binding with Unmethylated CpG-DNA of bacteria
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance: Binding with CpG-DNA of bacteria
Confidence Score: 5
Comment: TLR9 will bind with the unmethylated CpG-DNA of bacteria or pathogens.
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM4
Mechanism Class Name: Transport from ER to endosome and cleavage
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Transport from ER to endosome & cleavage
Confidence Score: 5
Comment: During this ligand recognition process, TLR9 got transported from Endoplasmic Reticulum to endosome via a shuttle protein UNC93b1, followed by a proteolytic cleavage to form active TLR9.
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM5
Mechanism Class Name: Signaling
Other Mechanism Class Name:
Modifer: Increased
Ontology: GO
Mechanism Instance:
Confidence Score: 5
Comment: Activated TLR9 intiates a signaling cascade by recruiting other proteins.
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM6A
Mechanism Class Name:
Other Mechanism Class Name: Activation of NF-kB pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: NF-kB pathway gets activated
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM6B
Mechanism Class Name:
Other Mechanism Class Name: Activation of MAPK pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: MAPK pathway gets activated resulting in AP1 nuclear translocation.
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: As a result inflammation is increased for Crohn's patients.
For Evidence: PMID:20490286
Against Evidence:

Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: Delayed wound healing
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: TLR9 deficient mice are shown to have delayed wound healing process. All these data are from mouse studies - so we used medium confidence color here.
For Evidence: PMID:20946144, PMID:22893852
Against Evidence:

Unknown Mechanism Module (MM) Annotations

Component ID: MM8
Comment: We are not sure about the mechanism for decreased abundance of VEGF and HES1 for Tlr9 deficient mouse.
For Evidence: PMID:22893852, PMID:20946144
Against Evidence:

Environmental Factor Annotations

Therapeutic Interventions Annotations

Component ID: TT1
Annotation Text: IRS-869, IMO-3100
Comment: Blocking the binding site of TLR9 ligands to the receptor. As TLR9 recognizes nucleic acid structures from pathogenic CpG-DNA, oligonucleotides with specific sequence can act as antagonist for endosomal TLR9, blocking the binding site of the receptor to the ligand, thereby blocking downstream signaling. These antagonists are names as immunoregulatory DNA sequence (IRS) (e.g., IRS-869) and immune modulatory oligonucleotide (IMO) (e.g., IMO-3100, which can significantly reduce the expression of inflammatory genes).
For Evidence: PMID:28769820
Against Evidence:

Component ID: TT2
Annotation Text: SMI ST2825
Comment: Blocking the intracellular signaling, utilizing endosomal location and modulating its pH. Small molecule inhibitors (SMIs), like chloroquine (CQ) (antimalarial drug), can cross cell membranes due to its small size and act on specific intracellular adaptor proteins. SMIs are weak bases and they modulate the pH by accumulating in acidic intracellular components, like endosomes – which leads to blocking of TLR9 signaling and reduction in cytokine productions. New SMIs (like, ST2825) have been developed which inhibits the dimerization of the adaptor protein, MyD88, thereby blocking the initiation of the signaling cascade for increased inflammation. Recently nano-devices are emerging as new TLR inhibitors, which have better bio-distribution and sustained circulation, due to their nanoscale sizes. One such nano-inhibitor is peptide-GNP (gold nanoparticle) hybrid system (e.g, P12) (GNP core coated with hexapeptide layer with increased chemical stability and good biocompatibility), which utilizes elevation of endosomal pH to block the downstream TLR signaling.
For Evidence: PMID:27728817
Against Evidence: