L24 - viral evasion of the Innate/interfon response Flashcards
what is the innate immune response accompanied by
inflammatory reponse
= induced by unnatural cell damage
= necrosis instead of apoptosis
ascociated with viral infections
what does the innate reponse recognise
PAMPs
pathogen acociated molecular properties
- unusaul polymeras on viral particles
- cell surface componets
- dsRNA
how many types of interferon are there
3
Type 1 interferons
IFN-⍺ = viral infection - dsRNA
IFN-b = viral infection - dsRNA
both produced by all cells but mainly dendritic
target all nucleated cells
Type 2 interferons
IFN-y = antigens,mitogens = IL-2 and IL-12
produced by T and Nk cells = activate/cause proliferation of cells
act on all nculeated cells
type 3 interferons
IFN-λ
= viral infection - dsRNA
produced by most cells but mainly dendritic
act on epithelial cells
whiuch type of inteferon is most important for viral infection
type 1
IFN-a and IFN-b
3 key steps in intereron system
- sensing
- signalling
- antiviral state
stages of interferon system simply
- sensing:
TLRs bind to PAMPs and induce Nf-kb - Signalling:
inteferons produced and released from cell then bind to adjacent cells - antiviral state:
activates Intereron-induced-genes
RIG-I like receptors vs TLRs
RLRs are found within the cytoplasm
TLRs are found on surfaces - cell surface membrane _ endosome surface
what detects PAMPs to induce Nf-kb
TLRs and RLRs
describe the intracellular signalling pathway following TLR activation
activated receptors due to phosphorylation on tyrosine residues
Myd88 recruited to receptor
eventual production of Nf-kb,IRF3 and IRF7
= interfon regulatory factors
name the 3 signaling molecules produced at the end of downstreaem signalling from TLRs/RLRs in viral infection mand results
Nf-kb:
pro-inflammatory cytokine production
IRF3 + IRF7:
Type 1 IFN produced
name the 4 most important TLRs for viral infections
TLR3
TLR7
TLR8
TLR9
name a TLR that is on the inside of a endosome and what it binds to
TLR3
dsRNA
how does IRF3 enter the nucleus following TLR activation
phosphorylatted and forms a dimer
= Type 1 IFN produced
How do RLRs cause signalling
cytoplasmic receptors
- RLR binds to dsRNA in the cytoplasm
= comformational change
- recruits MAVs protein via ‘CARD’ domains to mitochondria
= mitochondrial antiviral signalling protein
- actiavtion of MAVS causes downstream signalling
= production of IRF3, Nf-kb
describe cGAS role in stimulating pruction of iinteferon transcription factors
cGAS (cyclic GMP-AMP synthetase)
- cGAs binds to viraln DNA in cytoplasm
- produces cGAMP by linking an ATP + GTP
3.cGGAMP binds to STING
= stimulator of inteferon genes
- activated STINg moves to golgi activating the kinase = TBK1
- TBK1 produces IRF3 + Nf-kb
biphasic vs monophasic production of interferons
most cells is biphasic:
IFN-b is made which CAUSES IFN-a to be made
- IRF3 produced at the end of donstream signalling produces IRF7 from IFN-b gene
- IRF7 activates IFN-a
dendritic cells:
IRF7 is already present in inactive state = ‘primed’
= much faster and amplified production of IFNs
how many sibunits make up a IFN-receptor
2
= tyrosine kinase receptors - ITAMs
describe the downstream signalling when type 1 IFNs bind to receptors
- IFNs bind to their recptors causing phosphorylation of ITAMs
- STAT 1 + 2 dimerise and are phosphylated
= Signal Transduction and Activators of Transcription proteins
- inteferon stimulated gene factors (ISGFs) induced
- stimulate ISGs (inteferon stimulated genes)
= antiviral state
3 levels of the antiviral state
- mechanusms to prevent viral replication
- mechansism to killhost cell if infected
- mechaims to kill unifected cells in the area of infection
what ways can ISGs affect virals replicative life cycle
prevent entering
prevent unbcoating of viruses
block transcription
3 classical antiviral mechanisms
- dsRNA-dependant PKR pathway (protein kinase)
- The 2-5A system
- Mx pathway
describe the antiviral mechansism PKR - proteinb kinase
- PKR is an inactive protein kiase that recognises dsRNA
- binding causes autophosphorylation and dimerisation of 2x PKRs
- active dimer PKR phosphorylates elF2
= elongation factor in traqnslation
- elF2 binds irreversibly to elF2B
= protein sysnthesis halted in cell
describe the antiviral 2-5 A mechansism
- RNase L is a nuclease
- IFN induction causes mass production BUT remians inactive
- 2’-5’ Oligo(A) synthetase (OAS) produces adenylic acid when activated by dsRNA
- nucleotides activates RNase L
= cleaves viral RNA
describe the antiviral mechanism MxA
unlike PKR and RNase L
= Mx proteins are directed against specific viruses
2 different forms of Mx proteins that klive in cytoplasm - MxA + MxB
= interfere with different parts of lifecycle
name a way parmyxous virus has evolved to prevent ‘sensing’ stage of antiviral response
V protein blocks interecation of RLR with MAVS
= no downstream signalling
describe how the influenxaza virus has evolved to prevent ‘antiviral state’ part of the antiviral response
protein binds to PKR and prevents phosphorylation of elF2
why are intefrons not used more in drugs
has affects on healthy uninfeccted cells
- blcoks cell division
- alters transcription
= localasied ‘fire break’ to infection
