Pathophysiology of reinfection by exogenous HSV-1 is driven by heparanase dysfunction

Abstract

Limited knowledge exists on exogenous DNA virus reinfections. Herpes simplex virus-1 (HSV-1), a prototype DNA virus, causes multiple human diseases including vision-threatening eye infections. While reinfection with an exogenous HSV-1 strain is considered plausible, little is known about the underlying mechanisms governing its pathophysiology in a host. Heparanase (HPSE), a host endoglycosidase, when up-regulated by HSV-1 infection dictates local inflammatory response by destabilizing tissue architecture. Here, we demonstrate that HSV-1 reinfection in mice causes notable pathophysiology in wild-type controls compared to the animals lacking HPSE. The endoglycosidase promotes infected cell survival and supports a pro-disease environment. In contrast, lack of HPSE strengthens intrinsic immunity by promoting cytokine expression, inducing necroptosis of infected cells, and decreasing leukocyte infiltration into the cornea. Collectively, we report that immunity from a recent prior infection fails to abolish disease manifestation during HSV-1 reinfection unless HPSE is rendered inactive.

Prophylactic Vaccination and Intratumoral Boost with HER2-Expressing Oncolytic Herpes Simplex Virus Induces Robust and Persistent Immune Response against HER2-Positive Tumor Cells

“…Likewise, our preliminary findings in mouse models suggest that a prime and intratumoral boost interval of less than 5–6 weeks may diminish the effectiveness of the intratumoral oncolytic activity of oHSV-1. Nonetheless, reinfection with exogenous HSV-1 may happen [ 41 , 42 ], and a prior study has shown that inoculation of HSV-1 can produce exogenous reinfection in patients with frequent and recurrent herpes simplex infection [ 43 ]. This evidence supports the idea that regardless of HSV-1 seropositivity status, the prime and boost approach with HER2-expressing oHSV-1 should remain effective unless the initial priming occurs during the very early stages of HSV-1 exposure.…”

Exploring Heparanase Levels in Tears: Insights From Herpes Simplex Virus-1 Keratitis Patients and Animal Studies

“…The literature indicates that HPSE expression increases with disease severity in in vitro studies, and reducing HPSE activity inhibits viral shedding and disease outcome in animal models. 18 – 22 However, there is no information available on the role of HPSE in patients diagnosed with HSK or the tears of animal models of HSV keratitis. Taking into consideration that HPSE levels are significantly upregulated in HSV-1 infections, it is hypothesized to be a potential marker of HSV-1–related ocular infections.…”