Abstract
Analysis of a genome-scale RNA interference screen of host factors affecting herpes simplex virus type 1 (HSV-1) revealed that the mineralocorticoid receptor (MR) inhibits HSV-1 replication. As a ligand-activated transcription factor the MR regulates sodium transport and blood pressure in the kidney in response to aldosterone, but roles have recently been elucidated for the MR in other cellular processes. Here, we show that the MR and other members of the mineralocorticoid signalling pathway including HSP90 and FKBP4, possess anti-viral activity against HSV-1 independent of their effect on sodium transport, as shown by sodium channel inhibitors. Expression of the MR is upregulated upon infection in an interferon (IFN) and viral transcriptional activator VP16-dependent fashion. Furthermore, the MR and VP16, together with the cellular co-activator Oct-1, transactivate the hormone response element (HRE) present in the MR promoter and those of its transcriptional targets. As the MR induces IFN expression, our data suggests the MR is involved in a positive feedback loop that controls HSV-1 infection.
Highlights
Herpes simplex virus type 1 (HSV-1) is a neurotropic α-herpesvirus infecting over 90% of the global population
The virion-incorporated transcription factor VP16 initiates a temporal cascade of viral gene expression via the immediate-early genes ICP0, ICP4, ICP22, ICP27 and ICP47, which, with the exception of ICP47, act as transcription factors to regulate later stages of viral gene expression We investigated whether these viral transcription factors could activate the hormone response element (HRE) and mineralocorticoid receptor (MR) expression during herpes simplex virus type 1 (HSV-1) infection
In this paper we have investigated the mechanism by which the MR inhibits HSV-1 replication
Summary
Herpes simplex virus type 1 (HSV-1) is a neurotropic α-herpesvirus infecting over 90% of the global population. The nuclear receptor NR3C2 is the mineralocorticoid receptor (MR), and whilst it is expressed in a broad range of cell types, including the gastrointestinal tract, immune cells, brain, heart, bone, skin and skeletal muscle, the main target for its ligand mineralocorticoid is polarised epithelial cells[6] In these cells, the cytoplasmic complex of ligand:MR and chaperone proteins (HSP90 and the immunophilin FKBP4) translocates to the nucleus via the dynein microtubule network, where the MR induces expression of genes involved in sodium transport, such as the serum/glucocorticoid regulated kinase 1 (SGK1)[7]. SGK1, a major target for MR-responsive transcription, has been identified as a key regulator of T-cell differentiation mediated by the metabolic checkpoint kinase complex mTORC218 In this pathway, SGK1 simultaneously promotes TH2 differentiation whilst inhibiting TH1 cytokines, a phenomenon likely to have a significant negative effect on immune responses during viral infection. The induction of IFN-β expression by the MR highlights its role in a feedback loop of regulation of innate immune defence mechanisms against HSV-1 infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
