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!