HSV-2 inhibits type-I interferon signaling via multiple complementary and compensatory STAT2-associated mechanisms.

Abstract

Type-I interferon (IFN)-mediated responses are a crucial first line of defense against viral infections and are critical for generating both innate and adaptive immunity. Therefore, viruses have necessarily evolved mechanisms to impede the IFN response. HSV-2 was found to completely abolish type-1 IFN-mediated signaling via multiple STAT2-associated mechanisms. Although the extent and kinetics of this inactivation were indistinguishable between the various cell-lines examined, there were distinct differences in the mechanisms HSV-2 employed to subvert IFN-signaling among the cell-lines. These mechanistic differences could be segregated into two categories dependent on the phase of the HSV replicative cycle that was responsible for this inhibition: (1) early phase-inhibited cells which exhibited abrogation of IFN-signaling prior to viral DNA replication; (2) late phase-inhibited cells where early phase inhibition mechanisms were not functional, but viral functions expressed following DNA replication compensated for their ineffectiveness. In early phase-inhibited cells, HSV-2 infection targeted STAT2 protein for proteosomal degradation and prevented de novo expression of STAT2 by degrading its mRNA. In contrast, HSV-2 infected late phase-inhibited cells exhibited no apparent changes in STAT2 transcript or protein levels. However, in these cells STAT2 was not activated by phosphorylation and failed to translocate to the cell nucleus, thereby preventing transactivation of antiviral genes. In primary human fibroblasts, HSV-2 failed to fully degrade STAT2 and therefore, both early and late phase mechanisms functioned cooperatively to subvert IFN-mediated antiviral gene expression. Taken together, these results indicate the importance that HSV-2 has assigned to STAT2, investing significant genomic currency throughout its replicative lifecycle for continuous targeted destruction and inhibition of this protein.

• Authors: Ravi-Kumar Kadeppagari, Rebecca L Sanchez, Timothy P Foster
• Journal: Virus research (Virus Res) Vol. 167 Issue 2 Pg. 273-84 (Aug 2012) ISSN: 1872-7492 [Electronic] Netherlands
• PMID: 22634037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Interferon Type I
• STAT2 Transcription Factor
• STAT2 protein, human

Topics

• Animals
• Cell Line
• Herpesvirus 2, Human (immunology, pathogenicity)
• Host-Pathogen Interactions
• Humans
• Immune Evasion
• Interferon Type I (antagonists & inhibitors)
• STAT2 Transcription Factor (antagonists & inhibitors)
• Signal Transduction