Lecture 7: Pattern Recognition in Innate Immunity Flashcards
What are PAMPs?
Pathogen-associated Molecular Paterns (PAMP) are highly conserved molecules or molecular patterns in microbes. It allows discrimination between self and foreign (as well as differentiating between different microbes)
Recall the cellular sites of pathogen encounter.
Describe TLRs.
Toll-like receptors are germline-encoded receptors that specifically recognize PAMPs. It is always associated with membranes. The stimulation of TLR results in cytokine and chemokine secretion.
Important signal mediators include MyD88, IRAK4, TRAF-6, and IKK.
Recall the compartmentalized expression of TLR.
Explain an example of an outcome of the activation of membrane-bound TLR.
Activation of TLR4 leads to the activation of the enzyme cascade (MyD88-dependent response) leading to the release of inflammatory cytokines, such as IL-6. IL-6 have the following functions:
- Induction of acute-phase protein expression in the liver (CRP)
- Contributes to Th17 differentiation
- B cell differentiation
- Increased costimulatory molecule expression
- Systemic inflammatory responses (fever, fatigue)
Explain an example of an outcome of the activation of TLR in the endosome.
Activation of TLR3 leads to the activation of pathways where NF-kB or IRF3 enters the nucleus, transcriptionally activate genes and cause the release of IFN-alpha/beta (antiviral state). The following are the functions of IFN:
- Inhibition of viral protein synthesis
- Degradation of viral RNA
- Inhibition of virus assembly
- Increased costimulatory molecule expression
Recall cytosolic PAMP receptors and its significance.
Viruses replicate in the cytosol. Some bacteria can invade the cytosol (Listeria). Transfer of PAMPs from the endosome into the cytosol also occurs (Salmonella, E. coli).
All of these threats can be detected by NLR or RLR in the cytosol.
Describe RLR.
RIG-I-like receptors (RLR) recognize viral RNA present in the cytosol. It associates with the mitochondria and requires MAVS as an adapter molecule. It also induces the secretion of IFN-alpha/beta. This is the similar pathway as the endosome-TLR pathway activation.
Describe NLRs.
NOD-like receptors (Inflammasomes) associate with additional molecules to form large protein complexes in the cytosol. The protein complex incorporates pro-caspase-1 (results in cell death through pyroptosis), which when activated cleaves pro-IL-1ß into bioactive IL-1ß and IL-18.
What is pyroptosis?
Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. In this process, immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst and die.
Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host’s defensive responses.
Recall mechanism of inflammasome activation.
How does IL-1ß released from the cell?
After the cleavage of Pro-IL-1ß to IL-1ß by activated caspase-1, the IL-1ß still remains floating in the cytosol. However, the danger signals received that initially leads to the activation of caspase-1, also leads to the lysis of the host cell membrane (undergo pyroptosis). The released cytokines attract other immune cells to fight the infection and contribute to inflammation in the tissue.
Just see the different types of inflammasomes.
Note that the different inflammasomes detect different danger signals in the cell.
Recall the relevant PRR-cytokine pairs.
What are inflammasomes?
Activation and assembly of the inflammasome promote proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β and interleukin 18, as well as cleavage of Gasdermin-D, which induces a pro-inflammatory form of programmed cell death, referred to as pyroptosis, and is responsible for the secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane.
Describes the sequence of events that results in activation of the NLRP3 inflammasome
The NLRP3 inflammasome is a multi-subunit complex consisting of NLRP3, ASC and pro-caspase 1. Note that it requires a two signal model for the induction of inflammasome activity (both the activation of the NFkB pathway through TLR-signalling or membrane perturbations/potassium efflux).
TLR signals that activate NFκB seem important for both the redistribution of ASC forming the NLRP3 inflammasome and the production of pro-IL-1β (which is then cleaved by the activation of caspase by the NLRP3)
