Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection.
We previously demonstrated that IFN-beta transgene treatment protects mouse trigeminal ganglia (TG) cells from acute HSV-1 infection in vitro. However, IFN-alpha6 transgene treatment does not provide protection against acute HSV-1 infection in vitro, even though equivalent levels of IFN are expressed with both transgene treatments. In the present study we show that IFN-beta transgene treatment before acute ocular HSV-1 infection protects mice from HSV-1-mediated mortality, whereas IFN-alpha6 transgene treatment does not reduce mortality. Treatment with the IFN-beta and IFN-alpha6 transgenes was associated with increased expression of oligoadenylate synthetase (OAS)1a mRNA in the eye. However, protein kinase R mRNA was not up-regulated in the eye. In TG, only IFN-beta transgene treatment reduced infectious virus levels. Furthermore, in the absence of a functional OAS pathway, corneal HSV-1 Ag expression was more widespread, and the ability of IFN-beta transgene treatment to reduce infectious HSV-1 in eyes and TG was lost. Along with selective up-regulation of OAS1a mRNA expression in TG from IFN-beta transgene-treated mice, we found increased levels of phospho-STAT1. Likewise, p38 MAPK phosphorylation was increased in TG from IFN-beta transgene-treated mice, compared with both IFN-alpha6 and vector-treated mice. We also observed a time-dependent increase in JNK phosphorylation in TG from IFN-beta transgene-treated vs IFN-alpha6 and vector-treated mice. Our results demonstrate that IFN-beta is a potent antiviral cytokine that exerts protection against ocular HSV-1 infection via selective up-regulation of OAS1a mRNA in TG and by altering the phosphorylation of proteins in antiviral signaling cascades.
Austin
Bobbie Ann
BA
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Biomedical Sciences Building, 608 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA.
James
Cassandra
C
Silverman
Robert H
RH
Carr
Daniel J J
DJ
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000208:Acute Disease; D000818:Animals; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics; D016899:Interferon-beta / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D016849:Keratitis, Herpetic / Q000201:enzymology* / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis; D014162:Transfection; D019076:Transgenes; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000821:virology; D015854:Up-Regulation / Q000276:immunology; D014709:Vero Cells; D019562:Viral Load; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D016899:Interferon-beta; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease