From the previous R01 funding period we have generated compelling new evidence that human Heparanase-1 (HPSE), a heparan sulfate (HS) endoglycosidase, is a virulence factor responsible for triggering angiogenesis and inflammation in the eye during herpes simplex virus type-1 (HSV-1) infection. Our in vivo studies have shown that HPSE presence can significantly increase HSV-1 replication and severity of ocular disease with poor prognosis. Investigation of transcriptional and proteomic landscapes revealed a multitude of non-enzymatic roles for HPSE during HSV-1 infection and identified new druggable targets. Upon further investigation, we found that the significance of HPSE in corneal infection may not be limited to promoting viral pathogenesis only, but also in the induction of inflammatory cell death in a protein kinase B (Akt) dependent manner. Making things even more interesting and potentially more significant, our new preliminary data suggests that HPSE and Akt2 isoform phenocopy each other both in inflammatory cell death and deficiency in virus production. Therefore, based on our published observations of HPSE’s non-enzymatic roles and preliminary results, we hypothesize an important, yet interconnected regulatory role for HPSE and Akt2 in HSV-1 mediated ocular inflammation, nerve damage, and the resultant vision loss. We propose that their inhibition through small molecules can reduce disease severity and viral replication in the eye and reduce the incidences of viral encephalitis. This proposal will focus on understanding HPSE driven inflammatory cell death mechanisms and the role for Akt2 during HSV-1 replication, spread and disease pathology in the cornea. Successful completion of our studies will identify new and more effective HPSE and Akt2 inhibitors that can reduce inflammation as well as virus load without causing any adverse effects. Results generated through the proposed experiments will be broadly relevant, as aberrant HPSE activity has been implicated in a wide array of ocular pathologies and other neurodegenerative diseases and disorders such as multiple sclerosis and Alzheimer’s Disease.