Transcript Folie 1
Interferons
IFNa, IFNb…
• Cytokine family
important for
innate immunity
against viruses
• Three classes of
IFNs according to
the receptor used
• Type I IFNs
essential for
antiviral response
IFNl
IFNg
IFN-stimulated genes - ISGs
Antiviral Effect
Direct
Indirect
e.g. ISG15, MxGTPases, OASdirected RNaseL pathway,
PKR
• Induction of apoptosis
• Regulation of post-transcriptional
events (like RNA degradation)
• Regulation of post-translational
modifications
e.g. PRRs
• Detection of viral molecules
• Modulation of signalling
pathways and transcription
factors
• Increased IFN production
Protection from virus spread
ISG15
• Homologue to
Ubiquitin
• 158 putative target
proteins identified so
far (JAK1, STAT1,
PRRs, MxA, PKR,
RNAseL, …)
important role of
ISGylation in the IFNmediated antiviral
response through
modification of
components of the
host immune
response or viruses
Mx GTPases
• Expression strictly
regulated by type I and
type III IFNs
• Accumulate as
oligomers in cytoplasm
close to intracellular
membranes
• MxA monomers are
released to bind, trap
and degrade viral
components like
nucleocapsids
OAS/RNaseL pathway
OAS: 2‘,5‘-oligoadenylate synthetase
• constitutively expressed OAS
synthesizes 2’,5’-oligoadenylates after polymerization
triggered by viral dsRNA
• Binding of 2’,5’-oligomers to
the ankyrin repeats of RNasL
leads to its homodimerization
• Activated RNaseL cleaves
viral RNAs
• Type I IFNs upregulate OAS
expression
PKR
• Constitutively expressed (as
inactive kinase) at low levels
but induced by type I and
type III IFNs
• Direct activation by viral
RNAs or other ligands
followed by dimerization and
autophosphorylation
• Phosphorylation of EIF2a
blocks recycling of GDP
b
EIF2: eukaryotic translation initiation factor
protein translation inhibited
Apoptosis of the cell
Additional immune functions
• ISGylation: UBE1L is found to be a tumour
suppressor (deleted in almost all small-lung
cancers) possible mechanism how type I
IFNs regulate proliferation
• A polymorphism in OAS1 is associated with type
I diabetes
• PKR promotes degradation of IkB
-> activating NFkB
• PKR implicated in IgE class switching in B cells
-> viral infection might induce IgE-mediated
disorders like allergy or asthma
Future directions
Further details of the mechanisms of each
effector still have to be elucidated:
• Precise function of Mx proteins remains uncertain
GTPase activity?
• Contribution of alternative PKR substrates to immune
response is poorly explored
• Roles of PKR in regulation of inflammatory response
• Precise roles of different OAS proteins
• cataloguing of SNPs (single nucleotide polymorphisms)
in human and animals correlation to susceptibility to
viruses provide insight into gene function
• roles of these proteins in mediating adaptive immune
response potential to manipulate immunity, enhance
resistance to pathogens and disease or diminish
autoimmune responses
Summary
• Type I IFNs are essential for antiviral response -> ISGs
• Important role of ISGylation (ISG15) in the IFN-mediated
antiviral response through modification of components of
the host immune response or viruses
• Mx GTPase binds, traps and degrades viral components
like nucleocapsids
• RNaseL cleaves viral RNA with the help of an OAS
signal
• PKR inhibits protein translation and promotes apoptosis
• OAS and PKR also act as PRRs due to constitutive low
level expression
Viral replication is blocked
Thank you for your attention!