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

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posted on 05.08.2020 by David Shahnazaryan

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.


History

First Supervisor

Professor Conor C. Murphy

Second Supervisor

Professor Caroline Jefferies

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2018.

Published Citation

Shahnazaryan D. The role of viral regulatory protein ICP0 in herpes simplex type 1 keratitis. [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2018.

Degree Name

Doctor of Medicine (MD)

Date of award

30/06/2019

Programme

  • Doctor of Medicine (MD)

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