We will study the importance of two cellular receptors for herpes simplex 1 (HSV-1), herpes viral entry mediator (HVEM) and nectin-1, in the infection of the cornea and the establishment of latency by using mice knocked out (KO) for these receptors. Studies in cell culture and in vivo murine models of HSV infection indicate that HVEM and nectin-1 are the most efficient at mediating entry and most important in HSV pathogenesis. Reactivation of HSV-1 can lead to recurrent disease in the form of oral ulcers or more serious disease including encephalitis and herpes stromal keratitis (HSK). The precise mechanism of HSK pathogenesis is not fully understood, but factors known to contribute to disease include viral replication and the resulting immune response. We plan to study the outcome of corneal inoculation as well as examine which receptors function as HSV-1 entry mediators in susceptible tissues (corneal epithelium, corneal stroma, TG neurons, non-neuronal cells of the TG, immune cells, etc.). To fully understand disease pathogenesis and develop therapeutics, it is essential to understand the target tissues of HSV-1 in the eye. Our proposed studies will lay the foundation for further studies to determine whether infection of specific cell types, such as cells of the immune system, are important in HSV pathogenesis in the eye. By determining the precise cells infected by HSV in an ocular infection and the receptors utilized by the virus, novel treatment regimens can be developed that target those receptors. Such targeted therapies might attenuate primary infection and/or reduce inflammatory immune cells thereby preventing devastating sequelae including HSK, blindness, and encephalitis.
In Aim 1, we will characterize the role of HVEM and nectin-1 in primary HSV-1 infection of the cornea by determining whether HVEM and/or nectin-1 are required for primary HSV-1 infection of the cornea. We will also evaluate the importance of input viral load on the development of zosteriform disease and determine which cells in the eye and TG are infected during primary HSV-1 infection and whether or not those cells are expressing HVEM and/or nectin-1.
In Aim 2, we will determine whether HVEM and/or nectin-1 are necessary for HSV latent infection of the trigeminal ganglion.
Our specific aims are to identify the importance of the cellular receptors, HVEM and nectin-1, for HSV-1 infection of the eye. But more importantly how the use of these receptors contribute to herpes stromal keratitis (HSK). An understanding of the role for these receptors in HSK and how they contribute to disease will provide insight for the development of novel therapeutics for the treatment HSK which is the most frequent cause of corneal blindness in the US.
|Karaba, Andrew H; Kopp, Sarah J; Longnecker, Richard (2012) Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes. Proc Natl Acad Sci U S A 109:20649-54|
|Karaba, Andrew H; Kopp, Sarah J; Longnecker, Richard (2011) Herpesvirus entry mediator and nectin-1 mediate herpes simplex virus 1 infection of the murine cornea. J Virol 85:10041-7|