Pattern Recognition Receptors

Scientific concepts, discoveries, and nature phenomena

Innate immunity and threat detection

• Pattern recognition receptors (PRRs) are protein sensors located on or in cells that detect:
  • Pathogen-associated molecular patterns (PAMPs) → evidence of infection
  • Damage-associated molecular patterns (DAMPs) → evidence of tissue damage
• Detection triggers intracellular signaling cascades that coordinate immune responses.

PAMPs vs. DAMPs

• PAMPs

  • Molecular patterns specific to pathogens
  • Examples:
    • Bacterial cell wall components, e.g., lipid/lipoteichoic acid
    • Viral nucleic acids in characteristic forms:
      • Single-stranded RNA (ssRNA)
      • Double-stranded RNA (dsRNA)
  • Typically highly conserved to reduce the ability of pathogens to evolve away from recognition.

• DAMPs

  • Host molecules appearing in the wrong place/time
  • Example: extracellular ATP
    • ATP is normally intracellular; extracellular ATP implies cell damage
  • DAMPs commonly promote pro-inflammatory signaling.

Importance of cellular and receptor localization

• PRR effects depend on where both ligands and receptors are located.
• Receptor locations:
  • Cell surface PRRs: detect extracellular PAMPs/DAMPs
  • Cytosolic PRRs: detect intracellular microbial products
  • Endosomal PRRs: detect ligands brought into endosomes via endocytosis
• Polarization in intestinal epithelial cells
  • To prevent constant inflammation, many bacterial-sensing PRRs are positioned mainly on the basolateral side (not facing the gut lumen).
  • This helps them sense bacteria only after barrier crossing.

---

Toll-like receptors (TLRs): structure, signaling, and ligands

Structural organization

• Single-pass transmembrane proteins

  • Extracellular domain
    • Leucine-rich repeats forming a horseshoe/C-shape for ligand binding
  • Intracellular region
    • TIR domain for recruiting adaptor proteins

• Activation via dimerization

  • Can form homodimers or heterodimers with other TLRs
  • Dimerization brings together cytoplasmic tails for adaptor docking

Adaptor proteins and downstream signaling

• MyD88 pathway

  • Dimerized TLR tails recruit MyD88
  • Sequence of events:
    1. MyD88 recruits IRAK4, IRAK1, IRAK2
    2. IRAKs activate TRAF6
    3. TRAF6 (E3 ubiquitin ligase) polyubiquitinates itself and NEMO
    4. NEMO recruits/activates TAK1
    5. TAK1 activates the IKK complex
    6. IKK phosphorylates IκB, leading to IκB degradation
    7. NF-κB moves to the nucleus → induces inflammatory cytokines such as:
       • TNF-α
       • IL-6

• TRIF pathway

  • TRIF recruits TRAF6 and TRAF3
  • TRAF6 activates via RIP-1 → TAK1 → NF-κB activation (overlaps with MyD88 outcomes)
  • TRAF3 recruits TBK1 and IKKi
  • These phosphorylate IRF3
  • IRF3 dimerizes → nuclear translocation
  • IRF3 induces type I interferons (antiviral cytokines)

Examples of well-studied TLRs and what they detect

• TLR-2

  • Heterodimerizes with TLR-1 or TLR-6
  • Recognizes:
    • Bacterial lipoproteins
    • Lipoteichoic acid (Gram-positive cell wall component)

• TLR-3 (endosomal)

  • Recognizes double-stranded RNA (viral genome feature)
  • Endosomal sensing means it detects viral material that is endocytosed/phagocytosed, not necessarily cytosolic infection directly.

• TLR-4

  • Recognizes LPS (Gram-negative outer membrane component)
  • Notable features:
    • Uses all four adaptor proteins (as stated)
    • Requires accessory protein MD-2

• TLR-5

  • Expressed on myeloid cells and intestinal epithelial cells
  • Recognizes flagellin (flagellar protein subunit)

• TLR-7 (endosomal)

  • Recognizes single-stranded RNA
  • Localization rationale:
    • Endosomes normally contain ssRNA mainly after viral particle phagocytosis/endocytosis

• TLR-9 (endosomal)

  • Recognizes unmethylated CpG DNA
  • CpG definition (as described):
    • Cytosine adjacent to guanine, with cytosine at the 5’ end
  • Mammalian vs. microbial/viral distinction:
    • Mammalian CpG sequences are typically heavily methylated
    • Bacterial/viral DNA is less methylated → “unmethylated” CpG

---

NOD-like receptors (NLRs)

• Family function

  • PRRs that sense microbial products in the host cytoplasm, especially intracellular bacteria
  • Often expressed in epithelial cells and myeloid cells

• Domain architecture

  • Ancient pathogen sensors with leucine-rich repeats
  • Instead of a TIR domain, they contain an N-terminal CARD domain (a protein docking site for other CARD proteins)

• Ligand recognition and signaling

  • Recognize peptidoglycan components from both Gram-positive and Gram-negative bacteria
  • Upon detection:
    • RIPK2 binds the NLR’s CARD domain
    • Leads to downstream activation of TAK1, IKK, and NF-κB
  • Described as similar to the TRIF-dependent TLR pathway

---

RIG-I-like helicases (cytosolic antiviral nucleic acid sensing)

Role

• Detect viral nucleic acids in the cytosol

Key features

• A helicase-like domain that binds viral RNA
• Two N-terminal CARD domains for signal transduction

Examples

• RIG-I
  • Senses viral single-stranded RNA
• MDA-5
  • Senses cytosolic double-stranded DNA (as stated)

Outcome

• Activation drives production of type I interferons (antiviral cytokines)

---

DAMP sensing receptors and cross-recognition

Dedicated DAMP receptors

• P2X7
  • Senses extracellular ATP
• RAGE
  • Senses HMGB1
    • HMGB1 is a DNA-binding protein normally in the nucleus; becomes a DAMP when extracellular
  • Also senses S100 proteins
    • S100 proteins are cytosolic Ca²⁺-binding proteins

Cross-recognition by PRRs

• Many PRRs for PAMPs can also recognize DAMPs.
• Example:
  • TLR-4 can sense:
    • HMGB1
    • S100 proteins
    • “many other DAMPs”

General implication

• Broad PAMP/DAMP recognition enables rapid innate immune responses.

---

Methodologies / stepwise pathways (bullet outline)

TLR signaling via MyD88 → NF-κB (pro-inflammatory)

• TLR dimerization
• Recruit MyD88
• MyD88 recruits IRAK4/IRAK1/IRAK2
• IRAKs activate TRAF6
• TRAF6 ubiquitinates itself and NEMO
• TAK1 activation
• IKK activation
• IκB phosphorylation → degradation
• NF-κB moves to nucleus
• Transcription of inflammatory cytokines (e.g., TNF-α, IL-6)

TLR signaling via TRIF → IRF3/type I interferons (antiviral)

• TRIF recruitment of TRAF6 and TRAF3
• TRAF6 → RIP-1 → TAK1 → NF-κB activation (pathway overlap)
• TRAF3 recruits TBK1/IKKi
• Phosphorylate/activate IRF3
• IRF3 dimerizes and enters nucleus
• Type I interferon gene expression

NLR activation for intracellular bacterial sensing

• NLR recognizes peptidoglycan
• RIPK2 binds NLR CARD domain
• Activate TAK1 → IKK → NF-κB
• NF-κB-driven inflammatory signaling

RIG-I-like helicase activation for antiviral responses

• Helicase binds viral nucleic acid (via helicase domain)
• N-terminal CARD domains trigger signal transduction
• Induce type I interferons

---

Researchers or sources featured

• No specific researchers, historical scientists, or external sources are named in the provided subtitles.