Regulation of neurotropic herpesvirus productive infection and latency-reactivation cycle by glucocorticoid receptor and stress-induced transcription factors.

Abstract

Neurotropic α-herpesvirinae subfamily members, herpes simplex virus type 1 (HSV-1) and bovine herpesvirus 1 (BoHV-1), are important viral pathogens in their respective hosts. Following acute infection on mucosal surfaces, these viruses establish life-long latency in neurons within trigeminal ganglia (TG) and central nervous system. Chronic or acute stress (physiological or psychological) increases the frequency of reactivation from latency, which leads to virus shedding, virus transmission, and recurrent disease. While stress impairs immune responses and inflammatory signaling cascades, we predict stressful stimuli directly stimulate viral gene expression and productive infection during early stages of reactivation from latency. For example, BoHV-1 and HSV-1 productive infection is impaired by glucocorticoid receptor (GR) antagonists but is stimulated by the synthetic corticosteroid dexamethasone. Promoters that drive expression of key viral transcriptional regulatory proteins are cooperatively stimulated by GR and specific Krüppel like transcription factors (KLF) induced during stress induced reactivation from latency. The BoHV-1 immediate early transcription unit 1 promoter and contains two GR response elements (GRE) that are essential for cooperative transactivation by GR and KLF15. Conversely, the HSV-1 infected cell protein 0 (ICP0) and ICP4 promoter as well as the BoHV-1 ICP0 early promoter lack consensus GREs: however, these promoters are cooperatively transactivated by GR and KLF4 or KLF15. Hence, growing evidence suggests GR and stress-induced transcription factors directly stimulate viral gene expression and productive infection during early stages of reactivation from latency. We predict the immune inhibitory effects of stress enhance virus spread at late stages during reactivation from latency.