title: Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis.
abstract: Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. nandinis@stanford.edu
authors.forename: Nandini
authors.initials: N
authors.lastname: Sen
authors.forename: Xibing
authors.initials: X
authors.lastname: Che
authors.forename: Jaya
authors.initials: J
authors.lastname: Rajamani
authors.forename: Leigh
authors.initials: L
authors.lastname: Zerboni
authors.forename: Phillip
authors.initials: P
authors.lastname: Sung
authors.forename: Jason
authors.initials: J
authors.lastname: Ptacek
authors.forename: Ann M
authors.initials: AM
authors.lastname: Arvin
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D005434:Flow Cytometry; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008163:Luminescent Measurements; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000821:virology; D000077022:Survivin; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*
chemical_list: D000636:Aminosalicylic Acids; C107489:BIRC5 protein, human; D001557:Benzenesulfonates; D051034:Inhibitor of Apoptosis Proteins; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin