Cross-Seeding: Gut Microbiome-Derived Bacterial Curli and Fungal Amyloid Synergize with Host Aβ/α-Synuclein via TLR2/TLR1 Heterodimer Signaling
🧪 Overview
Commensal bacteria (E. coli, Salmonella) produce curli amyloid fibers encoded by the csg operon, while Candida and Saccharomyces produce glucan particles. These cross-seed mammalian amyloid conformations and independently engage TLR2/TLR1 heterodimers on microglia, triggering MyD88-dependent NF-κB and IRF5/IRF8 transcriptional programs that polarize microglia toward disease-associated microglia (DAM) phenotype. This paradoxically fails to clear amyloid and promotes pro-inflammatory cytokine release. SCFAs suppress IRF5 via GPR41/GPR43 and HDAC inhibition.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["TLR2/TLR1<br/>Heterodimer Recognition"]
B["CsgA Amyloid<br/>Bacterial Curli Fimbriae"]
C["IRF5 / IRF4<br/>Transcription Factor Activation"]
D["Pro-inflammatory<br/>Cytokine Response"]
E["csgAB Operon<br/>Fimbriae Expression"]
F["Neuroinflammation<br/>Mimics Alpha-Syn Pathology"]
G["Microglial<br/>Activation"]
H["Synaptic<br/>Impairment"]
A --> B
B --> C
C --> D
D --> G
E --> B
G --> H
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TLR2
No curated PDB or AlphaFold mapping for TLR2 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TLR2, TLR1, IRF5, IRF4, CsgA, csgABC operon from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TLR2, TLR1, IRF5, IRF4, CsgA, csgABC operon.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF germ-free 5xFAD mice are colonized with csgABC-expressing E. coli (ATCC 25922) or Candida glabrata compared to isogenic non-amyloid-producing mutants, THEN brain microglial IRF5 nuclear translocati | Increased IRF5 activation in microglia and elevated amyloid deposition in brains of colonized mice | — no observation — | pending | 0.65 |
| IF TLR2/TLR1 heterodimer signaling is pharmacologically blocked (using a TLR2 antagonist like C39 or genetic knockout in microglia) in 5xFAD amyloid mice, THEN microglial DAM marker expression (TREM2, | Reduced microglial DAM phenotype markers and lower pro-inflammatory cytokine levels in brain tissue | — no observation — | pending | 0.72 |
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |