Patter recognition receptors and CD14

Question 1

How do pattern recognition receptors work?

Answer 1

Recognise and distinguish host cells and pathogens by pathogen-associated molecular patterns (PAMPs)

Recognise host components released/generated as a result of cellular stress and tissue damage - damage associated molecular patters (DAMPs)

Question 2

How do innate immune receptors sense and respond to viruses?

Answer 2

Innate immune receptors sense and respond to viral challenges by detecting pathogen-associated molecular patterns (PAMPs) unique to viruses, such as viral RNA, DNA, or proteins, and initiating immune responses:

1. Detection by Pattern Recognition Receptors (PRRs):
   ○ Toll-like receptors (TLRs): Recognize viral nucleic acids, e.g., TLR3 (dsRNA), TLR7/8 (ssRNA), and TLR9 (DNA with unmethylated CpG).
   ○ RIG-I-like receptors (RLRs): Detect cytosolic viral RNA.
   ○ cGAS-STING pathway: Detects cytosolic viral DNA.
2. Signal Transduction:
   ○ PRR activation triggers intracellular signaling pathways, activating transcription factors like NF-κB, IRF3, and IRF7.
3. Cytokine and Interferon Production:
   ○ Induction of type I and III interferons (e.g., IFN-α, IFN-β) to establish an antiviral state in neighboring cells.
   ○ Production of pro-inflammatory cytokines (e.g., IL-6, TNF-α) to recruit immune cells.
4. Activation of Effector Mechanisms:
   ○ Induction of antiviral proteins like PKR and MxA.
   ○ Stimulation of natural killer (NK) cells and adaptive immune responses.

Question 3

How are TLRs activated?

Answer 3

Toll-like receptors (TLRs) are activated when they recognize and bind to specific PAMPs or DAMPs

Dimerization: Upon ligand binding, TLRs undergo conformational changes and form homodimers or heterodimers, depending on the TLR type (e.g., TLR2/1 heterodimers)

he cytoplasmic Toll/IL-1 receptor (TIR) domain of the TLR recruits adaptor proteins like MyD88 and TRIF

These activate downstream kinases, such as IRAKs and TBK1, leading to the activation of transcription factors like NF-κB, IRF3, or IRF7

Activated transcription factors promote the expression of pro-inflammatory cytokines, type I interferons, and other immune mediators to combat pathogens

Question 4

How is TLE activation regulated?

Answer 4

1. Accessory Molecules:
   ○ Accessory molecules like CD14, MD-2, and LPS-binding protein (LBP) facilitate the recognition of ligands (e.g., lipopolysaccharides for TLR4).
   ○ ST2 or SIGIRR, act as negative regulators, dampening TLR signalling to prevent overactivation.
2. Negative Feedback Mechanisms:
   ○ Negative regulators, such as SOCS (Suppressor of Cytokine Signaling) proteins, inhibit downstream signalling pathways.
   ○ MicroRNAs (miRNAs) can also suppress the translation of key signalling components.
3. Soluble TLRs:
   ○ Soluble forms of TLRs (e.g., soluble TLR2) act as decoys by binding to ligands and preventing them from interacting with membrane-bound TLRs, reducing overactivation of the immune response.

Question 5

What is the role of CD14

Answer 5

CD14 is a co-receptor that enhances the sensitivity of TLRs to specific ligands

Question 6

What is the role of soluble TLR2?

Answer 6

Soluble TLR2 (sTLR2) is a form of TLR2 that lacks the transmembrane and intracellular domains.

It acts as a decoy receptor, binding to TLR2 ligands (e.g., lipoproteins from bacteria) without initiating signaling, thus mitigating excessive TLR2-mediated inflammation.

sTLR2 can also modulate the immune response by sequestering ligands away from membrane-bound TLR2.