Doctor of Philosophy (PhD)
Veterinary Medical Sciences - Pathobiological Sciences
ABSTRACT Herpes simplex virus type 1 is a common neurotropic pathogen responsible for a multitude of human diseases ranging from mucocutaneous lesions, keratitis to life-threatening encephalitis. The hallmark of the HSV-1 life cycle is infection of sensory neurons, where the virus establishes a latent infection for the life of the host. Viral envelope glycoproteins play important roles in viral life cycle and virus-host interaction. Viral glycoproteins gK, gM, gE and the membrane protein UL11 have been shown to be important for virus assembly, egress and virus spread. To investigate the relative importance of each of gK, gM, gE and UL11 in infection of ganglionic neurons following ocular inoculation, recombinant viruses were constructed, characterized and used to infect mice via the ocular route. Results showed that gK plays the most important role in infection of ganglionic neurons following ocular inoculation in the mouse model. gK null viruses exhibited major defects in replication and cell to cell spread in tissue culture. To further investigate the role of gK in the pathogenesis of herpes keratitis and to delineate gK domains responsible for replication and neuroinvasion, recombinant viruses lacking the amino-terminus of gK were constructed. Characterization of the constructed viruses revealed that the amino terminus of gK is dispensable for replication in tissue culture; however, it is required for neuroinvasion and cell to cell spread. Moreover, the virus lacking the amino terminus in gK was unable to infect corneal epithelium and establish latency in the trigeminal ganglia after ocular inoculation of mice. In the above mentioned investigation, we have observed that lack of the amino terminus of gK is associated with lack of ocular disease in infected mice. Further investigation of this observation (still in progress) revealed a potential role for gK in the immunopathogenesis of keratitis. The research work presented in this dissertation is of paramount importance as it identifies gK as an important neurotropic determinant, and it delineates gK domains responsible for neuroinvasion and immunopathogenesis in vivo. This work may lead to the development of replication competent, safe vaccine vectors, and paves the way for the discovery of new therapeutics for herpes keratitis.
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Saied, Ahmad, "The Role of Herpes Simplex Virus Type 1 Glycoprotein K in Neuroinvasion and Immunopathogenesis of Herpes Keratitis" (2015). LSU Doctoral Dissertations. 3640.
Kousoulas, Konstantin Gus