Innate immunity Flashcards
Pathogen Associated Molecular Patterns are structures on microbes that are recognized by ___ on phagocytic cells
Pathogen Associated Molecular Patterns are structures on microbes that are recognized by pattern recognition receptors on phagocytic cells
PRRs (pattern recognition receptors) can be located in which 3 places in/on the phagocyte?
Locations of Pattern recognition receptors: intracellular (cytosolic and endosomal) and extracellular (on cell surface)
Some cytosolic PRRs include ___ (which recognizes damaged host cell products and bacterial cell wall lipids), RLR (which recognizes viral RNA) and ___ (which senses microbial DNA)
Some cytosolic PRRs include NLR - nod like receptors (which recognizes damaged host cell products and bacterial cell wall lipids), RLR - RIG like receptors (which recognizes viral RNA) and CDS - cytosolic dna sensor (which senses microbial DNA)
TLRs recognize ___ and C type lectin receptors recognize ___. Both are examples of extracellular PRRs
TLRs recognize bacterial cell wall lipids and C type lectin receptors recognize microbial sugars/polysaccharides. Both are examples of extracellular PRRs
Broadly, there are phagocytic PRRs such as ___ that are associated with phagocytosis and secreted PRRs which do what?
Some PRRs induce phagocytosis e.g. the mannose receptor, which doesn’t have too much signaling
Others are secreted (activate complement): like the MBL from the liver (note that this is an acute phase reactant); recall that this pathway also leads to opsonization of bacteria which also facilitates phagocytosis
What is an alarmin? Examples of alarmins are ___ (secreted by commensal bacteria) and ___ (promote chemotaxis).
T/F: Alarmins are only of microbial origin
Alarmins are also PAMPs and include defensins and chemokines
Falsehood. They can be both of human and microbial origin
T/F: PRRs can distinguish between pathogenic and non pathogenic PAMPs.
Endogenous TLR agonists are usually produced by ___ and include ___ which is normally ass’d with chromatin but can activate TLR4 and RAGE when a cell is necrosing and its nucleic contents are released
Endogenous TLR agonists (aka DAMPs) are released usually by dying cells e.g. high mobility group box1 (HMG Box1) is normally associated with chromatin? But when cell is undergoing necrosis and the HMG Box1 is released, it can activate TLR4 and RAGE which amplifies the innate immune response
___, endogenous TLR agonists that are deposited in the joints are necessary for inflammasome activation >> leads to gout
Uric acid crystals, endogenous TLR agonists that are deposited in the joints are necessary for inflammasome activation >> leads to gout
What are the cell wall differences between gram +ve and gram -ve bacteria?
T/F: TLR2 binds to LPS on gram neg bacteria
T/F: Gram -ve bacteria don’t have peptidoglycan
Recall that Gram +ve bacteria have peptidoglycan on their cell wall, which is the main PAMP for TLR2
Gram –ve bacteria have LPS in their outer membrane (sits on top of a very thin peptidoglycan layer)
Falsehood. TLR2 >> Peptidoglycan >> Gram +ve
Falsehood. Gram -ve bacteria do have peptidoglycan but its a really thin layer
**you’re positive because you only have peptidoglycan; but you’re negative because you have LPS too which is too much weight so you just feel negative all the time**
Briefly describe PRR signaling and the processes that lead to upregulated gene transcription/translation (hint: NF-KB)
The agonist binding to the receptor which is usually associated with some adapter protein (typically a heterodimer) induces a conformational change that results in recruitment of a kinase >> phosphorylates downstream kinases (here = mitogen activated protein kinases MAP-K or Ik-B/NF-KB complex in the cytosol) >>phosphorylation of transcription factors or NFKB sits on specific promoter sequences >> gene transcription/translation
**the action of most cytokine signaling is NFKB driven**
The downstream effects of m-phage-LPS binding include production of pro-inflammatory lipid metabolites (e.g. TXA2 and PGE2), ___ and ___.
What is the body’s response under normal circumstances vs pathological circumstances?
Downstream effects of m-phage/LPS interactions: production of pro-inflammatory lipid metabolites (PAF, TXA2,PGE2); ROS; cytokines + chemokines
Under normal circumstances, the physiological response improves host immunity and adaptive immune response (adjuvant effect)
Under pathological circumstances e.g. bacterial sepsis, you get a cytokine storm >> circulatory collapse/multiple organ failure >> shock/death (there’s also feedback so you can activate IFN-y which, in the presence of LPS, upregulates this cytokine storm problem so that makes things worse)
Describe the basic model of TLR signaling.
What are the roles of MyD88 and NF-KB?
TLR binding and IL-1 receptor binding leads to recruitment of the MyD88 adapter protein >> phosphorylation of downstream kinases >> phosphorylation of IkB/NFKB complex >> upregulation of gene transcription (see image for specific proteins you need to memorize)
**MyD88 adapter stopped working so I RAKed up a bunch on loans and ran into TRAFic. I couldn’t TAK it anymore so I went to go see Ik-B-NFKB together but I ended up only seeing NF-KB to get my genes upregulated**
___ forms a heterodimer with TLR1 or TLR6 while all other TLRs are homodimers.
___ is the co-receptor ass’d with TLR4
Which TLRs are the endosomal TLRs?
TLR2 forms heterodimers w/ TLR1 or TLR6, while all the others homodimerize
TLR4 doesn’t bind the DAMP directly but instead uses a co-receptor (MD-2) (binding of a DAMP then causes recruitment of another TLR4-MD2 complex then you form the homodimer then you proceed to the usual signaling)
**other extracellular: 5, 10, 11**
Endosomal TLRs:
3: dsRNA
7: ssRNA
8: Resiquimod
9: CpG DNA
What do the endosomal TLRs recognize?
(see image below)
What’s the difference between TLR4 signaling on the cell surface vs on the endosome?
What TLR only activates the TRIF pathway and not the MyD88 pathway?
If TLR4 is on the endosome, it recruits TRIF >> activation of IRF3 (interferon regulatory factor 3) >> production of Type I IFNs
*note that TLR3 ONLY activates the TRIF pathway and NOT the MyD88 pathway*
How does TLR signaling result in inflammasome-mediated inflammation? (recall: TLR signaling = gene transcription. Which gene is upregulated and what does thatdo/how is that related to the inflammasome?)
TLR signaling creates upregulation of pro-IL1 beta gene >> cleaved into active IL1-B by caspase 1 when second signal activates the inflammasome (e.g. uric acid crystals) and caspase 1 is turned on >> mature IL1-B is secreted and acts on IL-1 receptor to mediate inflammatory response
Describe the formation of the phagolysosome following phagocytosis.
What actually ends up killing the ingested microbes?
(see pic below for 1st answer)
Inside the phagolysosome:
ROS (H202 and superoxide); produced by NADPH oxidase during respiratory burst
RNI (NO + superxide >> peroxynitrite)
Enzymes (proteases/nucleases/lysozymes)
Explain the pathway below:
Phagocytosis is accompanied by uptake of oxygen; the NADPH oxidase converts the oxygen to superoxide anion (microbicidal). This can be converted to hydrogen peroxide (H2O2) by the superoxide dismutase. H2O2 is also microbicidal.
Catalase breaks down H2O2 to water. Many pathogens make catalase to evade being killed.
Myeloperoxidase (in the presence of halide ions and H2O2) leads to insertion of halide ions into the bacterial cell wall and killing of the microbe by osmolar disruption.
THESE ARE TIGHTLY COUPLED REACTIONS – so, a mutation in any of the enzymes that are part of the coupled reaction can lead to decreased microbial killing.
Describe the downstream effects of LPS and IFN-y binding
IFN-gamma and LPS synergize to activate macrophages classically.
Classically activated m-phages are both microbicidal and tumoricidal
Describe how LPS and IFN-y binding to their receptors on macrophages leads to tumor cell killing
LPS binds the TLR4 and IFNy binds the IFN-y receptor on the macrophage >> transcription of iNOS >> mature iNOS converts arginine to NO >> NO downregulates Krebs cycle, dna synthesis and ETC in the tumor cell
___ disease results from NADPH oxidase deficiency
Chediak-Higashi syndrome is a defect in ___
___ is a group of disorders where interaction of leukocytes with vascular endothelium is disrupted; due to autosomal recessive mutation that results in faulty expression of ___
Chronic granulomatous disease results from NADPH oxidase deficiency
Chediak-Higashi syndrome is a defect in phagosome and lysosome fusion
Leukocyte adhesion deficiency is a group of disorders where interaction of leukocytes with vascular endothelium is disrupted; due to autosomal recessive mutation that results in faulty expression of CD18
A deficiency in ___ results in recurrent Neisseria infections due to lack of MAC formation
___ deficiency results in defective TLR signaling >> recurrent gram positive bacterial infections
___ can increase sensitivity to certain infections
A deficiency in C8 results in recurrent Neisseria infections due to lack of MAC formation
IRAK4 deficiency results in defective TLR signaling >> recurrent gram positive bacterial infections
TLR polymorphisms can increase sensitivity to certain infections
Describe how the following bugs can evade killin by the immune system
Pneumococci
Staphylococci
Neisseria meningitidis
Describe how the following bugs evade killing by the host immune system
Streptococcus
Pseudomonas
Neisseria gonorrheae
___ on the macrophage binds LPS
CD14 (co-receptor) for TLR4
