SurveyThe virus battles: IFN induction of the antiviral state and mechanisms of viral evasion
Section snippets
JAK–STAT signaling
Studies of intracellular signaling by the IFN system led to characterization of the JAK–STAT pathway (reviewed in [7], [8]). Both IFN-α/β and IFN-γ stimulate signaling in target cells through interaction with the extracellular domains of transmembrane proteins of the cytokine receptor class [9]. Such receptors are characterized by cytoplasmic effector domains that lack recognizable catalytic function. Instead, they interact specifically with cytoplasmic protein tyrosine kinases of the Janus
Lessons from gene knock-out mice
Most of the components of IFN-dependent JAK–STAT signaling have been disrupted by gene targeting in transgenic mice (reviewed in [42]). These include the genes for IFN-β and IFN-γ [43], [44], both chains of both the IFN-α/β receptor and the IFN-γ receptor [45], [46], [47], [48], [49], JAK1, JAK2, and TYK2 [50], [51], [52], STAT1, STAT2, and IRF9 [3], [53], [54], [55], and IRF1 and IRF2 [56], [57]. These in vivo studies have supported the models of IFN signaling developed from biochemical and
Antiviral pathways induced by IFN
There are several hundred genes transcriptionally regulated by IFNs [71]. Among them, three families of IFN-inducible genes have been extensively studied with respect to their antiviral activities. These genes encode the double-stranded RNA-activated protein kinase (PKR), the 2′,5′-oligoadenylate synthetases (OAS), and the Mx protein(s). These proteins actively participate in inhibiting viral replication by different mechanisms.
Evasion of the IFN system by viruses
The IFN system is one of the earliest defense mechanisms against virus infections acquired during evolution by higher eukaryotes. Not surprisingly, millions of years of coevolution between hosts and their pathogens has resulted in the acquisition of mechanisms by most viruses to inhibit, at least to some extent, the host IFN system. Interestingly, it appears that different viruses antagonize IFN-mediated defense responses by inhibiting distinct steps in IFN-activated signaling and antiviral
Conclusions
Signal transduction from IFN receptors through the JAK–STAT pathway to mediate rapid and robust transcriptional induction of genes encoding antiviral proteins is an elegant, highly evolved system that protects animal cells from viral infection. Natural or experimental deletion of the individual components of this defense system has demonstrated the profound importance of the IFN system to innate immunity. The co-evolution of viruses with their hosts has given rise to a remarkable variety of
Acknowledgements
We thank our colleagues for helpful discussions and for providing unpublished data. Work in the authors' laboratories was funded in part by National Institutes of Health Grants AI28900, AI46503, AI46954, and AI48204.
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