Role of Heparanase in Herpes Simplex Virus Pathogenesis

Herpes simplex viruses (HSV-1 and -2) remain among the most prevalent human pathogens worldwide. While a majority of individuals exposed show little or no symptoms of disease, it remains unclear why others progress to serious complications such as recurrent infection, corneal lesions and encephalitis. These findings combined with the inadequacies of our current antiviral therapies and failures of all vaccine clinical trials point to the importance of a deeper understanding of the host factors involved in viral pathogenesis. With this goal, we show here that heparanase (HPSE) is one such component that is upregulated upon infection and acts as a host-encoded virulence factor essential for the invading pathogen. Best known for its roles in driving inflammation and cancer metastasis, at the extracellular matrix HPSE is the major regulator of heparan sulfate (HS), an important attachment receptor for many human viruses. We demonstrate that herpesviruses enhance HPSE levels at the plasma membrane to facilitate release of newly produced viral particles and increase infectious spread. Furthermore, we show that upon infection, increased levels of active HPSE are found at the nucleus, where it drives multiple hallmark processes of viral pathogenesis through transcriptional regulation of pro-inflammatory signals. Finally, by merging temporal viromics analysis with targeted molecular investigation, we reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple defense mechanisms. Given that HPSE is a well-conserved protein throughout evolution and that HS is a common viral receptor, a grasp of this host factor’s interactome and pathogenic functions may provide important targets for antiviral and anti-inflammatory treatments.