Role of Optineurin in Ocular Herpes Infection

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DESCRIPTION (provided by applicant): Herpes simplex virus type-1 (HSV-1) can cause irreversible damage to the human cornea and is capable of infecting virtually all major cell types in the eye. The virus is also considered a cofactor in causation of secondary glaucoma and is thought to play similar roles in certain degenerative diseases of the human brain. A lytic infection by HSV-1 is known to down regulate host protein synthesis to favor viral protein production. Very limited information is available on the host proteins that are up-regulated during the infection. This proposal is focused on understanding the function(s) of a cellular protein, optineurin (OPTN), an autophagy adapter protein, in HSV-1 infection of the eye. The gene encoding OPTN has been implicated in glaucoma and amyotrophic lateral sclerosis. Our preliminary data shows that OPTN is widely expressed in human and murine corneas. We have also found that OPTN is up-regulated in response to HSV-1 infection of human corneal epithelial (HCE) cells and transient over-expression of OPTN in HCE cells results in an increased number of plaques formed by HSV-1. This exploratory proposal will test the hypothesis that OPTN is a key to a productive infection of the human corneal cells by HSV-1. We propose to explore two independent roles for OPTN in HSV-1 infection. The first Aim will focus on the possibility that HSV-1 infection interferes with OPTN phosphorylation by TANK binding kinase-1 (TBK1), which in turn results in the inhibition of autophagy induction and interferon production, and viral replication ensues. The second Aim will examine a role for OPTN, via interaction with myosin VI, in the transport of newly made HSV-1 glycoproteins and fusion of virus-laden vesicles with the plasma membrane that facilitate the virus release from cells. Overall, our studies are expected to shed new lights, and for the first time, implicate OPTN as an important co-factor in HSV-1 infection of the cells in the cornea.