The Syndecan-1 Paradox in HSV-1 Infection and Pathogenesis

Herpes simplex virus type 1 (HSV-1) is a globally prevalent neurotropic virus that establishes lifelong latency within trigeminal ganglionic neurons and undergoes periodic reactivation, resulting in recurrent mucocutaneous and ocular disease. In severe manifestations, HSV-1 infection can progress from herpetic epithelial lesions to herpetic stromal keratitis and, in rare cases, encephalitis, vision impairment, or blindness. Importantly, disease severity extends beyond viral replication; it is critically governed by host determinants that regulate viral entry and dissemination, epithelial barrier integrity, and the resolution of inflammatory responses. Syndecan-1 (SDC1), a major heparan sulfate chain-bearing proteoglycan, traditionally characterized as a primary attachment receptor that facilitates HSV-1 binding and entry through its heparan sulfate chains. However, its broader functional contribution to viral pathogenesis, maintaining tissue integrity during infection, and immunoregulation remains elusive. This dissertation interrogates the paradoxical role of SDC1 in HSV-1 infection and demonstrates that, beyond serving as a viral attachment factor, SDC1 functions as a critical regulator of inflammation and tissue homeostasis, restraining excessive immune activation and thereby modulating disease severity. Using complementary in vitro systems and in vivo models of ocular HSV-1 infection, this work demonstrates that HSV-1 actively induces SDC1 shedding from infected epithelial cells. This shedding enhances viral release and exacerbates tissue damage. Mechanistic analyses identify the viral neurovirulence factor ICP34.5 as a key driver of this process through the JNK-EGR-1-HPSE axis, leading to glycocalyx remodeling and enhanced viral spread. Importantly, pharmacological inhibition of JNK signaling significantly reduces SDC1 shedding, limits viral dissemination, preserves epithelial integrity, and attenuates disease severity, underscoring the therapeutic potential of host-directed, resistance-refractory antiviral strategies. In contrast to the pathogenic consequences of SDC1 shedding, genetic ablation of SDC1 uncovers its indispensable protective functions during HSV-1 infection. SDC1 deficiency results in enhanced viral spread, disruption of epithelial junctions, compromised blood-brain barrier integrity, persistent neuroinflammation, impaired immune resolution, and the development of autoimmune-like sequelae. These findings highlight the critical role of SDC1 in maintaining barrier homeostasis and regulating inflammatory responses necessary for tissue recovery following infection. Together, this dissertation defines SDC1 as a molecular switch in HSV-1 infection, wherein viral exploitation of SDC1 shedding promotes pathogenesis, while loss of SDC1 expression leads to uncontrolled inflammation and autoimmunity. By resolving this paradox, this work provides a unified framework for understanding HSV-1-induced tissue damage and identifies SDC1-associated signaling pathways as promising targets for next-generation antiviral and immunomodulatory therapies.

Author dc:creator

• Divya Kapoor (1995793)

• Herpes simplex virus type 1 (HSV-1)
• Biology, Virology

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995211.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995211