Innate Immunity Flashcards
innate immunity (2)
- first line of defense in the immune response
- non-specific
innate immunity: general characteristics of immunity (5)
- barriers keep harmful materials from entering the body
- direct engulfment of pathogen (phagocytosis) leads to destruction of the pathogen
- secretion of chemokines and cytokines
- sense the threat and type of threats using TLR receptors
- shape the adaptive immune response
what kind of barriers are involved in mucosal defense (2)
- chemical
- mechanical
what is mucus produced by
- sub-epithelial goblet cells
how does mucus contribute to innate immunity (2)
- traps bacteria
- contains transferrin, lactoferrin, anti-microbial peptides and lactoperoxidase
what are the three steps to eliminating infection in mucosal defense (3)
- plasma exudation
- immune exclusion
- immune elimination
mucosal defense: plasma exudation (2)
- plasma is exuded from blood vessels into the mucus site during infection
- plasma can contain serum proteins, such as bactericidal antibodies and complement
mucosal defense: immune exclusion (2)
- antibodies neutralize the bacteria
- prevent binding of bacteria to host receptors for uptake
mucosal defense: immune elimination (2)
- breach in epithelial layer results in exposure to cells of the immune system
- elimination of bacteria by immune cells
what is one of the first lines of mucosal defese
- nasopharynx contains mucus and cilia to prevent bacteria from entering lungs/intestines at all
what are some ways that the bacteria can protect itself from the host innate immune system (5)
- prevent complement-mediated lysis
- prevent phagocytosis
- escape autophagy
- prevent lysosomal fusion
- prevent cytokine release
why did the innate immune system evolve
- to recognize invariant structures in pathogens
what are the invariant structures we recognize on pathogens called
- pathogen associated molecular patterns (PAMPs)
what are some examples of PAMPs (3)
- carbohydrate-based (dsRNA, bacterial DNA, PG)
- lipid-based (lipoproteins, LPS)
- proteins (flagella)
what does the innate immune system use to detect pathogens (2)
- pattern-recognition receptors (PRRs)
- recognize conserved epitopes
what PRR recognizes the lipid A portion of LPS (a PAMP)
- TLR4 and MD-2 co-receptor
what groups of molecules do PRRs recognize (2)
- PAMPs from pathogens
- DAMPs released from damaged cells
what cells are PRRs found on (5)
- dendritic cells
- macrophages
- monocytes
- neutrophils
- epithelial cells
what occurs after innate immune recognition of pathogen (2)
- direct engulfment of pathogen, leading to pathogen destruction
- secretion of cytokines and chemokines that shape the adaptive immune response
TLR 4: ligand
- LPS
TLR4 components (3)
- ectodomain binds lipid A
- transmembrane region
- cytoplasmic region contains a toll-interleukin 1-receptor (TIR) domain
how does TLR4/MD-2 recognize LPS (4)
- LPS bind to LPS-binding protein, a free protein
- complex interacts with CD14, a membrane receptor
- CD14 delivers LPS to MD-2, which attaches to a TLR4
- TLR4/MD-2/LPS complex dimerizes with another complex
what are important domains on TLR4 for dimerization (2)
- charged PO4- interface
- neutral acyl chain interface
TLR4/MD-2/LPS: how does signaling work after dimerization (3)
- TIR domains come in close proximity
- domains act as a scaffold to recruit adaptor proteins
- activates two signaling pathways
what are the two signaling pathways activated by TLR4 (2)
- MyD88 pathway
- TRIF pathway (MyD88-independent pathway)
TLR4/LPS: what protein orchestrates signaling
- the TIRAP/Mal protein
what kind of protein is TIRAP/Mal
- sorting adaptor protein
what kind of protein is MyD88
- signaling adaptor protein
TLR4/LPS: MyD88 pathway, up to MyD88 activity (3)
- TIRAP/Mal binds to TIR domain of TLR4
- MyD88 binds TIRAP
- MyD88 associates with series of kinases
TLR4/LPS MyD88 pathway: what occurs due to MyD88 associating with kinases (2)
- activation of I kappa B kinases (IKK-1 and IKK-2)
- results in phosphorylation of IKB
TLR4/LPS MyD88 pathway: how is IKB normally found in the cytosol
- found in complex with NFkB
TLR4/LPS MyD88 pathway: what is NFkB
- transcription factor
TLR4/LPS MyD88 pathway: what occurs after IKB phosphorylation
- IKB is marked as degradation target for proteasomes
- NFkB is released and translocates to the nucleus
TLR4/LPS MyD88 pathway: what is the result of NFkB translocation to the nucleus (3)
- expression of pro-inflammatory cytokines
- tumour necrosis factor (TNF-α), IL-12, IL-6
- increased expression of co-stimulatory molecules
TLR4/LPS: what is a general result of the MyD88 pathway
- activation of adaptive immunity
TLR4/LPS: when is the TRIF pathway triggered
- after endocytosis of dimerized TLR4/MD-2/LPS complex into an endosome
TLR4/LPS pathway: first half of the TRIF pathway (3)
- TRAM adaptor binds to TIR domain of TLR4
- TRIF binds to TRAM and leads to series of signaling events (phosphorylation events)
- results in activation of IRF-3 TF and translocation to the nucleus
TLR4/LPS TRIF pathway: what is the results of IRF-3 translocation to the nucleus (3)
- leads to expression of interferon-β (a type-I interferon)
- activates expression of interferon-β inducible genes and chemokines
- late induction of NFkB
TLR4/LPS TRIF pathway: what is the benefit of the delayed response
- ensure system isn’t overwhelmed, causing more damage
TLR4/LPS TRIF pathway: what is the general result of this pathway
- influence the adaptive immune response
what can be the result of uncontrolled innate immune responses (3)
- endothelial damage leading to multiple-organ system failure
- acute respiratory distress syndrome (ARDS)
- disseminated intravascular coagulation (DIC)
what is ways that bacteria can avoid the TLR4/LPS signaling pathways (2)
- innate mimicry to interfere with TLR signaling
- lipid A modifications in LPS to affect recognition by PRRs
TLR4/LPS: innate mimicry (2)
- bacterial genomes contains genes encoding TIR-like domains
- make TIR-containing proteins (TCPs)
what types of bacteria practice innate mimicry against the TLR4/LPS pathway
- uropathogenic E. coli (UPEC)
monocyte model: WT bacteria vs TCP mutant
- WT induced lower levels of pro-inflammatory cytokines, whereas mutants induced higher levels
mouse model: WT bacteria vs TCP mutant
- mutant was less virulent compared to the wild type
innate mimicry: how does TCP function (3)
- binds MyD88
- reduces normal signaling in response to infection
- reduces inflammation
how can lipid A be modified in LPS (2)
- number of acyl chains
- charge of lipid A
where can lipid A modifications be made in LPS (2)
- modifications of acyl chains in the outer membrane
- modifications of phosphates in the inner membrane
endocytosis (2)
- ingestion of large particles (such as bacteria)
- uptake of fluids or macromolecules in small vesicles
phagocytosis (2)
- ingestion of large particles
- “cell eating”
pinocytosis (2)
- uptake of fluids or macromolecules in small vesicles
- “cell drinking”
