Heparanase in Herpes Simplex Virus Pathogenesis and Disease

University Of Illinois At Chicago, Chicago IL

Investigators

Linked publications, trials & patents

Abstract

Very little information exists on host molecules as virulence factors that directly promote viral disease manifestations. Heparan sulfate (HS) proteoglycans are ubiquitously expressed and heavily implicated in health and disease. In humans, a variety of pathological conditions including inflammation and neovascularization can result from uncontrolled degradation of HS by a highly specific endoglycosidase, heparanase (HPSE). Since HS is an important constituent of the extracellular matrix, increased HPSE enzymatic activity leads to an enhanced release of cytokines and growth factors promoting neovascularization, inflammation, and tissue damage, which are also typical of herpes simplex virus-1 (HSV-1) disease pathologies. HS serves as a common attachment receptor for numerous viruses, and we recently reported a loss of HS from the cell surface and a coinciding increase in HPSE expression and higher enzymatic activity during HSV-1 release from human cells. Our central hypothesis for the current proposal is that HSV-associated disease pathologies can result from the upregulation of HPSE expression and higher enzymatic activity. We propose to use the cornea as a unique model system to establish a role for HPSE in HSV-induced inflammation, angiogenesis and related tissue damage. We have generated evidence that HPSE expression is increased via HSV-mediated activation of nuclear factor (NF)-kB, and propose to use organotypic cornea cultures and novel proteomics assays to address this association and search for other potential regulators of HPSE upregulation upon HSV-1 infection as Aim 1 of this proposal. Given recent evidence tying higher HPSE levels with inflammation and angiogenesis, Aim 2 will define the role of human HPSE in driving HSV disease pathologies. We will determine the levels of pro-inflammatory and angiogenic factors after enhancing HPSE activity via over expression of a constitutively active form of HPSE, or knockdown of the proenzyme. We will also assess new vessel formation and corneal scarring as well as immune cell proliferation after modulating HPSE expression and activity levels in murine corneas. With results obtained from these studies, we hope to establish higher HPSE activity as a trigger for viral disease manifestations, identify new host or viral factors that signal HPSE up-regulation, and ultimately validate new target(s) in the treatment of HSV-induced inflammation and angiogenesis. Our findings will be first of its kind implicating HPSE in a viral disease and for developing new strategies to combat viral and non-viral diseases.