Herpes Simplex Virus 1 Targets IRF7 via ICP0 to Limit Type I IFN Induction

Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV‑1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi‑pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti‑viral and pro‑inflammatory cytokines. However, given that HSV‑1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV‑1 to downregulate the anti‑viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target

The role of viral regulatory protein ICP0 in herpes simplex type 1 keratitis

Herpes simplex keratitis (HSK) is the commonest cause of infectious blindness in the developed world. It is caused by herpes simplex virus type 1 (HSV‐1) and is characterised by recurrent episodes of infection and immune‐mediated corneal inflammation that lead to significant loss of vision. Following transmission of HSV‐1 the virus is initially suspended in the tear film, where it encounters a multi‐pronged defence comprising enzymes, complement, immunoglobulins and crucially, a range of anti‐viral and pro‐inflammatory cytokines. HSV‐1, however, is able to overcome innate immune responses, to establish lifelong latency and to reactivate throughout susceptible individual’s lifetime with the potential of causing irreversible damage to the sight. The crucial roles of viral regulatory protein ICP0 in the pathogenesis of HSV‐1 infection is well established. ICP0 is important for the virus’s ability to cause a productive infection, to establish a latent state and to successfully reactivate. However, the molecular mechanisms behind these processes are largely unknown. The aim of this study was to investigate the interactions between ICP0 and key elements of type I IFN pathway and to identify possible targets that contribute to viral survival. Our Luciferase studies have demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of TLRs 3, 4 and 7 which are known to be involved in host antiviral defences. Further co‐transfection experiments have identified IRF7, a crucial driver of IFN‐ as a potential target for ICP0. IRF7 stability experiment has confirmed that IRF7 is targeted by ICP0 for degradation in a dose dependent fashion. This finding is another step towards better understanding of the pathogenesis of herpes simplex keratitis (HSK) and may become a potential therapeutic target for HSK.<br

Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target

Systemic IL-1β production as a consequence of corneal HSV-1 infection-contribution to the development of herpes simplex keratitis

This study sought to identify potential therapeutic targets in herpes simplex keratitis (HSK) patients with active and inactive infection by investigating peripheral cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum were prepared from healthy controls and HSK patients during active infection or following treatment (inactive infection). Serum antibody titres were determined by ELISA. Protein expression levels were analysed by Western blot. Cytokine levels were determined by multiplex ELISA. Active corneal herpes simplex virus type 1 (HSV-1) infection resulted in significantly elevated peripheral levels of IL-1β in HSK patients compared to healthy controls, and remained significantly increased following treatment. Elevated production of IL-1β in inactive patients was associated with significantly increased levels of IRF3 and STAT1, key proteins involved in promoting anti-viral immune responses. Our data suggest that inflammation persists beyond the period that it is clinically evident and that enhanced peripheral production of IL-1β may have implications for HSV-1 viral clearance in active and inactive HSK patients