Factors Influencing Ocular Pathogenesis Caused by HSV-1: Viral Genetics and the wnt/β-catenin Pathway

Abstract Under pathological conditions like herpes simplex virus-1 (HSV-1) infection, host-pathogen interactions influence the responses to infection and dictate the course of disease progression. Of note is the contribution of viral strain genetic variances, which play an instrumental role in host responses. Here we show that viral genomic variations are capable of generating an acquired entry receptor bias usage leading to disparate immunopathogenic responses and ultimately disease outcomes. Whole genome sequence analysis of two clinical isolates of ocular HSV-1 from patients presenting distinct pathologies demonstrate large degree of coding sequence variability. Further sequence analysis demonstrated glycoprotein D of one particular strain yields a favorable interaction with HVEM, a member of the tumor necrosis family that has been shown to mediate ocular immunopathogenesis through the induction of T cell response that promotes HSK. Ocular murine infection with this clinical isolate displayed unique properties of heightened virulence and neuroinvasiveness, characterized by a robust T cell response, accompanied by other immune cell infiltrates leading to loss of corneal integrity and dissemination to the central nervous system, causing eventual mortality. This shows that viral genomic variations are capable of generating an acquired entry receptor bias usage leading to disparate immunopathogenic responses and ultimately disease outcomes. Furthermore, host-pathogen interactions lead to major reconstruction of the host protein network, which also contributes to the dysregulation of signaling pathways and disease onset. To this end, we investigate the consequences of the dysregulation of the wnt/β-catenin pathway and host factors contributing to this. We find that virus-induced upregulation of heparanase (HPSE) leads to the activation of the β-catenin pathway and this generates a cellular environment conducive to viral replication. We further explore β-catenin as a drug target against HSV-1 infection and explore the therapeutic potential of targeting this pathway. Our findings indicate robust antiviral properties of drugs targeting β-catenin which includes PRI-724, iCRT14 and KYA1797k. For HSV-1 specifically, current antivirals are not able to abolish the virus from the host, leaving patients susceptible to episodes of viral reactivation. Investigating virus-host interactions and deciphering between the differential contributions of disease development can provide insight to developing enhanced therapeutic approaches.