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.
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TLR2 yet. Search RCSB →
Median TPM across 13 brain regions for TLR2, TLR1, IRF5, IRF4, CsgA, csgABC operon from GTEx v10.
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.
No resource usage or linked notebooks recorded for this hypothesis yet.
| 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 |