![]() ![]() This complex binds to the IFN stimulated response element (ISRE) and in concert with recruited transcriptional co-activators such as p300/CBP then drives IFN-stimulated gene (ISG) transcription. Phosphorylation of STAT2 enables reruitment of STAT1 and release of the phosphorylated STAT1-STAT2 heterodimer bound to IRF-9. Type I IFN signaling starts by activation of the IFN-α/β receptor (IFNAR) and subsequent activation of the IFNAR1-associated TYK2 and IFNAR2-associated JAK1, with consequent recruitment of STAT2. 10.1371/001 Figure 1 Scheme for IFN signal transduction. These observations indicate that the IFN-signaling pathway is subject to a so-called “rheo-STAT” adjustment wherein down-regulation causes increased susceptibility to viral infection whereas up-regulation might lead to increased efficiencies for IFN-stimulated gene (ISG) expression and control of infection. Moreover, modification of STAT1 to a form) that improves the efficiency of IFN signal transduction can result in improved control of viral infection. Consequently, genetic loss of STAT1 function causes a marked susceptibility to viral infection in mice and humans –. And within this IFN system, which is similarly complex, the STAT1 transcription factor is remarkable as a central component that is critical for the functional activity of each type of IFN ( Figure 1). Although antiviral defense exhibits significant complexity and redundancy, one system that stands out as a useful target for improvement is the one based on the action of interferons (IFNs). An alternative to agents that specifically and directly target the virus itself is the possibility of improving natural host defense against a broad range of viruses. Similarly, the efficacy of antiviral therapeutics can often be limited by pathogen resistance as another sign of the difficulty in keeping up with rapidly evolving viral genomes –. For these types of infections, vaccines can still be ineffective due to new and emergent strains and can exhibit significant off-target effects. ![]() There has been significant progress in the development of vaccines and therapeutics against viruses, but there are still major gaps in medical therapy for some of the most common types of viral infections.
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