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
