Harro Frauendorf. Introduction. Infection: microbes vs. host Viruses try to secure a niche for replication Host must limit pathogen's advance Type 1 interferons are key players many members: IFN- α / β Virus evolved tricks to avoid antiviral effects of IFNs (co evolution).
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constitutively expressed in a subset of cells, the plasmacytoid dendritic cells (PDCs),
(TLR2 and TLR4 can also detect viral products such Core, NS3
or F-protein, Env-protein.)
(named independently by four different groups as mitochondrial antiviral signaling protein (MAVS), IFN-b promoter stimulator 1 (IPS-1), virus-induced signaling adaptor (VISA), and CARD adaptor–inducing IFN-β (CARDIF))
type 1 IFNs regulate a range of immune responses through the type 1 IFN receptor
IFN-a receptor 1 (IFNAR1) and IFNAR2
subunit dimerization and activation of kinases that associate with their cytoplasmic tails: the Janus-activated kinase 1 (JAK1) and tyrosine kinase 2 (TYK2)
tyrosine phosphorylation activates the signal transducers and activators of transcription 1 and 2 (STAT1 and STAT2), to form a trimeric STAT1-STAT2-IRF9 complex, also known as IFN-stimulated gene factor 3 (ISGF3)
STAT1 homodimer complex, known as the IFN-γ–activated factor (GAF)
Both complexes translocate to the nucleus and bind to DNA regulatory sequences containing IFN-stimulated response elements (ISREs) and IFN-g–activated sites (GAS)IFN-mediated effects on defense
Protein kinase R
2′,5′-oligoadenylate synthetase 1
The MxA protein accumulates in the cytoplasm on intracellular membranes (such as the endoplasmic reticulum, ER) as oligomers formed by association between the leucine zipper (LZ) domain and central interactive domain of the protein.
Following viral infection, MxA monomers are released and bind viral nucleocapsids or other viral components, to trap and then degrade them.myxovirus-resistance A (MxA)
Protein kinase R is constitutively expressed, and is also induced by type I interferons (IFNs).
The kinase accumulates in the nucleus and cytoplasm as an inactive monomer, which is activated directly by viral RNAs (and by several other ligands
Following activation, PKR monomers are phosphorylated and dimerize to form the active enzyme.
a crucial function of PKR in viral defence is the inhibition of translation by phosphorylation of eukaryotic translation initiation factor 2α (EIF2α).Protein kinase R (PKR)
OAS1 is expressed at low constitutive levels and is upregulated by type I interferons (IFNs).
OAS1 protein accumulates in the cell cytoplasm as an inactive monomer.
activation by viral double-stranded RNA (dsRNA), the enzyme oligomerizes to form a tetramer
Synthesize of 2′,5′-oligoadenylates activate constitutivelyexpressed inactive ribonuclease L (RNaseL).
The binding of 2′,5′-oligoadenylates to RNaseL triggers the dimerization of enzyme monomers, through their kinase-like domains, and this then enables RNAseL to cleave cellular (and viral) RNAs.2′,5′-oligoadenylate synthetase 1 (OAS1)
viral IFN antagonists focus inhibition on at least one of three key pathways: the IRF3, the JAKSTAT, and the PKR pathways
RIG-I and mda5 can't detect viral ds RNA.
blocks both TLR3- and RIG-I–mediated activation of IFN.
accessory V and W proteins bind to these factors and prevent their activation