The roles of inflammation, STAT transcription factors, and nerve growth factor in viral reactivation and herpes keratitis.
Nerve growth factor (NGF) has an inhibitory effect while inflammatory cytokines may stimulate herpes simplex virus (HSV) reactivation. NGF binds to its receptor trkA on terminal axons and signals the neuron cell body in the ganglion. Many cytokines may also signal neurons through their specific receptors, affecting STAT transcription factors within the cell bodies. We studied the effects of trigeminal ganglion (TG) explantation, a powerful HSV reactivation stimulus, on the NGF/trkA and the JAK/STAT signaling pathways. Immunohistochemistry and gel shifting experiments were performed using anti-STAT, anti-trkA, or negative control antibodies on mouse TGs. The expression of neuronal trkA was greatly reduced or eliminated by 3 days postexplantation. In contrast, the expression of STAT1, STAT3, and STAT5b, as well as phosphotyrosine-STAT3 were relatively preserved in these explanted TGs. Gel-shifting experiments indicated that TG nuclear extracts bind specifically to the HSV-1 LAT promoter, an important viral gene that regulates reactivation. STAT1, but not STAT3 or STAT5b, was detected as a component of this LAT binding complex. These studies suggest that the inhibitory effects of NGF/trkA signaling are lost after TG explantation while STAT expression is maintained, allowing HSV-1 reactivation to proceed.
Kriesel
John D
JD
University of Utah School of Medicine, Departments of Internal Medicine and Ophthalmology, Salt Lake City, Utah 84132, USA. jkriesel@med.utah.edu
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000254:growth & development*; D006801:Humans; D016849:Keratitis, Herpetic / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D020932:Nerve Growth Factor / Q000502:physiology*; D020917:Receptor, trkA / Q000502:physiology*; D012008:Recurrence; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000821:virology; D014775:Virus Activation
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D020932:Nerve Growth Factor; D020917:Receptor, trkA