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83 Cards in this Set
- Front
- Back
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Compare and contrast innate and adaptive immunity
Origin |
I: Primitive, ancient
A: More recent |
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Compare and contrast innate and adaptive immunity
Recognition |
I: Chemical pattern
A: Specific epitopes |
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Compare and contrast innate and adaptive immunity
Development |
I: Rapid and immediate
A: Slow (1-2 weeks) |
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Compare and contrast innate and adaptive immunity
Messengers |
I: Cytokines
A: Cytokines |
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Compare and contrast innate and adaptive immunity
Memory |
I: None
A: Long (lifetime) |
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Compare and contrast innate and adaptive immunity
Presentation |
I: Direct recognition by TLRs or other receptors
A: Processing, synapse, Dual system: Humoral and CMI, Th |
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Compare and contrast innate and adaptive immunity
System |
I: Simple, direct recognition
A: Highly complex |
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What are the cellular anti-viral mechanism of defense? (3)
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IFN
Innate IR Adaptive IR |
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What is the IFN response?
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1st line of defense
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What is the innate IR comprised of?
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Phagocytosis by macs
Cell killing by NK cells |
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What does the adaptive IR do?
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Humoral immune response
-->Ab production by B cells --> Killing by CD8+ Tcells of infected cells |
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What is the defining ability of IFNs?
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Confer an antiviral state on cells
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Why are IFNs essential for the survival of higher vertebrate?
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They provide an early line of defense vs viral infections
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What happens to mice with individually inactivated alpha/beta/gamma receptor?
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They exhibit variably reduced resistance to infection and altered immune responses
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Which 3 paths are activated after viral infection
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1) TBK-1 & IKKe
2) NF-kB 3) AP-1 |
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What are TBK-1 and IKK-e?
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Viral kinases that P IRF3 on specifc serine residues
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What happens once IRF3 is P?
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It opens up and allows its translocation to the nucleus
Get recruitment of CBP Get T of target genes |
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How is IRF3 expressed?
Where? |
Expressed constitutively in all cells
Responds to infections in all non-immune cells |
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What mediates NF-kB?
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IKK complex
When IK-Ba is P, iNF-kB gets degraded by the proteasome |
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What happens once NF-kB is free to go to the nucleus?
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Get T of important IFN genes
** Especially Inflammatory genes |
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What are some of the chemokines made during the primary events?
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IFN-B/a: goes on to activate 2ry events
RANTES, IL-15: chemokines for adaptive IR |
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What happens to the lvls of IFN at the end of the 1ry event?
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Low lvls of IFN
==>These low levels can bind the IFN-receptor |
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What do these low levels of IFN do?
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Signals to STAT after binding the IFN-receptor
Get ISGF3 complex ISGF3 binds ISRE and get IRF-7 |
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What is the IRF-7 response?
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Amplification response, requires the initial wave of IFN produced by IRF-3 activation
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What happens to the 2nd population of cells after infection?
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Has both IRF3 and 7 induced IFN in the cytoplasm
This population of cells have IRF3/7 heterodimers (instead of homodimers) Get amplification of IFN All subtypes of IFN-a are produced and get induction of all IFN-induced genes =>Get full blown antiviral response |
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Which cells have RIG-1?
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All cells
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What does RIG-I do?
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REcognizes viral RNA in the cell cytoplasm
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What does RIG-1 recognize?**
What does Mda5 recognize?** |
RIG-1: RNAs with 5' tri-P elements (5'PPP-AVA)
Mda5: rec'z long dsRNA |
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What do the RLRs signal through?
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MAVS
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What is MAVS? Why is it important?
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Mitochondrial adaptor which is essential for downstream signalling
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What happens when the RLR is bound?
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Structure opens up
Exposes CARD domain Triggers MAVS dimer To oligomerize, MAVS need to localize to OMM |
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How does the Influenza virus inhibit its recognition by the IS?
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Uses its ptn NS1 to block RIG-I activation by blocking the CARD domain
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How does HCV inhibit recognition by IS?
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Uses its ptns NS3/4A to cleave MAVS away from mitochondria and disrupts downstream signalling
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How does the Hantavirus inhibit its recognition by the IS?
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Gw ptn disrupts interaction btw TRAF3 and TANK
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What is the point of these viruses inhibiting the MAV/IFN system?
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Impair IRF3/7 signalling
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Describe the activation of the JAK-STAT pathway, for type I IFN
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When IFN-a/B binds IFN-a receptor
Need Jak1 and Tyk2 and P STAT1 & 2 Recruit IRF9, which is present in its inactive form in the cytoplasm Forms a trimeric complex that binds ISRE DNA recognition mediated by IRF9, whose DBD rec'z ISRE |
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Describe the Jak-Stat path for type II IFN (IFN-y)?
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Acts throught Jak 1 &2
Only activates STAT 1 (get a homodimer) STAT1 binds to GAS (y-activated signal) =>Get activation of immune genes |
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To which path do all IFNs signal?
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Jak/STAT path
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What happens when IFN-y binds the /IFN-y Receptor?
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Get a tetramer (2 Jak1 and Jak2)
Jak1 and 2 P each other When Stat1 is recruited, can be P by Jak P Stat makes STAT1 dimers |
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What happens when Type I IFN bind the IFNa/B receptor?
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Jak1 and Tyk2 P each other
Dock inside the receptor is P by Tyk2 and STAT2 is recruited to it STAT2 is P by Jak1 This causes STAT-1 to go to P-STAT2 and also gets P by Jak1 Form STAT heterodimer that will bind IRF and lead to downstream signalling |
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How can the Jak-Stat path be negatively regulated?
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1) De-P by Tyr phosphatases SHP and SHIP
2) Degradation by Ub-proteasome systems 3) Dominant negative STATs 4) CIS/SOCS/SSI family: send ptns for proteasomal degradation |
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What is the point of negatively regulating the Jak-STAT path?
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Save the host from damage from an overreactive IS
Viruses take adv of this |
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What happens if viruses activate SOCS in an untimely manner?
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System shuts off too quickly and can get tumour viral replication
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What are the ways to inhibit Jak-STAT path?
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1) Sequestration of Stat1: SeV, using its C and V ptns, prevents ass't with IFN receptor, inhibiting downstream signalling
2) Inhib. of P: Mumps virus (V ptn) 3) Proteasome-mediated degradation: send STAT-1 directly to the proteasome (SV5, MuV, NDV, HTLV-1) 4) Inhib. of nuclear translocation of STAT: unknown if Mumps does this |
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What are the different mechanisms that makeup the IFN antiviral fct?
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1) 2'5' oligoadenylate synthetase (OAS)
2) RNase L 3) PKR 4) Mx ptn 5) HLA class I histocompatibility Ags |
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What are Mx ptns?
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GTPases that block vital components by trapping them
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What are the different mechanisms that makeup the IFN antiviral fct?
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1) 2'5' oligoadebylate synthetase (OAS)
2) RNase L 3) PKR 4) Mx ptn 5) HLA class I histocompatibility Ags |
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What are Mx ptns?
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GTPases that block vital components by trapping them
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Describe the PKR path
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PKR induced by IFN
Activated by viral dsRNA ATP-dependent Once P, PKR P eIF2a This inhibits ptn synthesis --> Get cell cycle arrest and inhibition of viral ptn synthesis --> PKR path can also lead to apoptosis |
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Describe the 2'-5' OAS system
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IFN induces OAS
Activated by viral dsRNA Needs 3 ATP to form the 2-5 oligoadenylate, which binds RNase L Activates RNaseL which cleaves RNA Any viral RNA that sees this RNaseL will be cleaved This leads to inhibiton of ptn synthesis because there aren't anymore viral mRNA to use |
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How does RNaseL amplify the antiviral response?
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Cleaves the RNA into little pieces that can cause an IR
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Describe PKR
What kind of kinase? Expression level? What induces it? |
Ser-Thr kinase
Expressed at low levels in all cells IFN inducible |
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How does PKR control ptn translation?
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By P the substrate of eIF-2a
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How does inactive PKR become active?
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When it binds dsRNA, it undergoes dimerization and auto-P
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Describe the PKR structure
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Regulatory domain--- Dimerization domain---- Kinase domain
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What does the PKR structure look like when its inactive?
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N-term is folded over the C-term and inhibits its kinase activity
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Describe the N-term of PKR
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Has 2 dsRNA binding motifs
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What happens when PKR binds dsRNA?
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N-term binds the dsRNA
This allows structure to open Allows dimerization and transP of the kinase, which leads to their activation |
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How does PKR inhibit translation initiation?
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eIF-2a usually uses GTP to load the met-tRNA onto the ribosome and allow Tl initiation
When PKR is activated, P eIF-2a and traps it in a state where it is bound to GDP (can't exchange GTP for GDP and is .: inactive so it can't put met-tRNA onto the ribosome --> No Tl initiation |
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What is the antiviral effect of PKR due to?
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P of the alpha subunit of eIF2
--> When its P, get formation of inactive complex that involves eIF2-GDP and recycling of eIF2B |
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What happens when PKR P eIF2?
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Get rapid inhibition of translation
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What happens if PKR is overexpressed?
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Get apoptosis
-->This mechanism dependent on Bcl2 and ICE |
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How can some viruses protect themselves from PKR path?
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1) Hide dsRNA by coating it (NS1)
2) Encode dsRNA viral homologues that bind PKR and inactivate it (instead of activating it) 3) deP eIF2a so there can be Tl 4) Directly bind PKR and prevent dimerization or its kinase activity |
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What does ISG56 do?
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Inhibit ptn synthesis
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When is ISG56 produced?
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Following infection, IFN stimulation causes production of the ISG56 mRNA
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How does ISG56 inhibit ptn synthesis?
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ISG56, after being produced binds eIF3 and prevent s ribosomal assembly
Inhibits pre-initiation complex = Tl inhibition and viral growth inhibition |
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What happens in the 2'-5' OAS path?
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IFN-inducible 2-5A synthetases are stimulated by dsRNA to produce a series of short 2',5'-oligoadenylates that activate RNase L
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What happens when the 2'5' OAS is activated?
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Extensive cleavage of ssRNA
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Where are the 2-5 synthetases encoded?
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By multiple genes that stay in different parts of the cell
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What does 2-5A bind?
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Bind to the inactive, monomeric RNase L, causing formation of the homodimeric active enzyme
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Is RNase L activation reversible?
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Yes
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Describe how RNase L is activated
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Viral dsRNA activates OAS ptns
OAS1 becomes an active tetramer Tetramer produces oligodenylates, which bind RNaseL N-terminal Activates RNaseL and lets it open up Active RNAse acts on ssRNA, which dampens viral replication |
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What happens to the short pieces of RNA that are made by the OAS path?
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Stimulate the RIG-I path
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Describe structure of RNaseL
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N terminal: Regulatory repressor involved in 2-5A binding
C terminal: region of ptn kinase homology and the ribonuclease domain --> Isolate C terminal of RNaseL cleaves RNA in the absence of 2-5A |
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What happens to RNase L-null mice?
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Have a deficiency in both the anti-EMCV effect of IFN and in several apoptotic paths
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What does the N term structure have that makes it inhibitory?
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Ankyrin repeat
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What happens to RNase-L is it is missing its N- terminal?
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Get constitutively active RNase L that doesn't need binding to polyadenylated to be activated
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How can the virus prevent the 2-5A from working?
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1) dsRNA binding ptns: hides the viral RNA
2) 2-5A derivatives: mimic the adenylation and inhibit RNase L activation 3) Induce RNase-L inhibitor ptn |
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What are targets of Mx ptns (ptns that are IFN-inducible)?
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Negative strand RNA
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What are the 2 types of Mx?
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Murine Nuclear ptn MX1: suppresses the growth of influenza and tick-born Dhori viruses
Human Cytoplasmic ptn MxA: inhibits the growth of influenza, VSV, measles, etc |
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What does MxA do?
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Sequesters viral components
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How does MxA work?
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Monomers spontaneously assemble into oligomers
Oligomers trap viral components and oligomerize them into speckle structures that are ass't with ER mbs (Sequesters NP ptn) |
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What happens if MxA is mutated?
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Not as good at containing the viral titer
Fails to interact with NP ptn |
