Although the HSV-1 gene(s) that is involved in eye disease is not yet known, we have demonstrated previously that immunization of mice with gK, but not with any other known HSV-1 glycoprotein, significantly exacerbates CS and facial dermatitis following ocular HSV-1 infection of different strains of mice. This exacerbation of the CS occurs independently of the virus strain used for infection or the strain of mouse. As gK is essential to HSV-1 infectivity, we analyzed its contribution to CS using recombinant viruses with two extra copies of gK and found that, similar to gK immunization, mice infected with this recombinant virus have elevated levels of CS. The exacerbation of disease is of particular interest as it would appear to mimic the clinical disease process typical of individuals with a history of HSV-1 recurrences. This provided the basis for our innovative approach to the problem of identifying potential therapeutic targets for prevention of ocular HSV-1 infection and HSV-1- induced CS. Our progress during the past funding period provides novel insights into the potential mechanisms by which gK may regulate primary infections and CS. We have now shown that: (1) The cleaved form of gK binds to signal peptide peptidase (SPP) and increases virus replication (Preliminary Studies) and (2) The 8-mer within the signal sequence of gK following cleavage by SPP up-regulates the CD8+CD25+ responses in the cornea of infected mice leading to exacerbation of CS. Based on these data, we have formulated the central hypothesis that the pathogenic effects of gK during primary infection are mediated by two different, but inter-related, mechanisms in which the cleaved form of gK exerts its activities by binding to SPP leading to higher levels of virus replication, while the 8-mer within the signal sequence of gK following cleavage by SPP up-regulates CD8+CD25+ T cells in vivo leading to greater levels of eye disease. We propose to test this hypothesis through the following Specific Aims:
Aim 1 : Test the hypothesis that binding of the cleaved form of gK to SPP plays a major role in virus replication and thus infectivity in vitro and in vivo.
Aim 2 : Test the hypothesis that the 8-mer (ITAYGLVL) within the signal sequence of gK binds to MHC-I on DCs and mediates up-regulation of CD8+CD25+ T cells, thus leading to exacerbation of CS in ocularly infected mice.
Previously we have reported that HSV-1 gK exacerbate eye disease in infected mice. In Our Preliminary Studies we have shown that gK binds to signal peptide peptidase (SPP). We now plan to demonstrate that blocking this interaction will reduce virus replication in the eye and reduce eye disease in HSV-1 infected mice.
|Matundan, Harry H; Mott, Kevin R; Akhtar, Aslam Abbasi et al. (2015) Mutations within the pathogenic region of herpes simplex virus 1 gK signal sequences alter cell surface expression and neurovirulence. J Virol 89:2530-42|
|Mott, Kevin R; Maazi, Hadi; Allen, Sariah J et al. (2015) Batf3 deficiency is not critical for the generation of CD8Î±âº dendritic cells. Immunobiology 220:518-24|
|Allen, Sariah J; Mott, Kevin R; Matsuura, Yoshiharu et al. (2014) Binding of HSV-1 glycoprotein K (gK) to signal peptide peptidase (SPP) is required for virus infectivity. PLoS One 9:e85360|
|Dumitrascu, O M; Mott, K R; Ghiasi, H (2014) A comparative study of experimental mouse models of central nervous system demyelination. Gene Ther 21:599-608|
|Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) CD8Î± dendritic cells drive establishment of HSV-1 latency. PLoS One 9:e93444|
|Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71|
|Allen, Sariah J; Mott, Kevin R; Ghiasi, Homayon (2014) Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo. Exp Eye Res 123:8-15|
|Allen, Sariah J; Mott, Kevin R; Ghiasi, Homayon (2014) Overexpression of herpes simplex virus glycoprotein K (gK) alters expression of HSV receptors in ocularly-infected mice. Invest Ophthalmol Vis Sci 55:2442-51|
|Matundan, Harry; Mott, Kevin R; Ghiasi, Homayon (2014) Role of CD8+ T cells and lymphoid dendritic cells in protection from ocular herpes simplex virus 1 challenge in immunized mice. J Virol 88:8016-27|
|Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS One 9:e87617|
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