Herpesvirus Entry Mediator Binding Partners Mediate Immunopathogenesis of Ocular Herpes Simplex Virus 1 Infection

• Published in: mBio 2020-05, Vol.11 (3)
• Main Authors: Park, Seo J, Riccio, Rachel E, Kopp, Sarah J, Ifergan, Igal, Miller, Stephen D, Longnecker, Richard
• Format: Article
• Language: English
• Subjects: Animals; BTLA; CD160; Cornea - immunology; Cornea - pathology; Cornea - virology; Disease Models, Animal; Female; Herpesvirus 1, Human - immunology; Herpesvirus 1, Human - physiology; herpesvirus stromal keratitis; Host Microbial Interactions - immunology; Host-Microbe Biology; HSV; HVEM; immunopathogenesis; Inflammation; Keratitis, Herpetic - immunology; Keratitis, Herpetic - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Receptors, Tumor Necrosis Factor, Member 14 - immunology; Receptors, Tumor Necrosis Factor, Member 14 - physiology; Signal Transduction; T-Lymphocytes - immunology; Virus Internalization
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00790-20

Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4 T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus entry mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated. In this study, we investigated the role of HVEM and its binding partners in mediating the T cell response using a murine model of ocular HSV-1 infection. By infecting mice lacking the binding partners, we demonstrated that multiple HVEM binding partners were required for HSK pathogenesis. Surprisingly, while LIGHT , BTLA , and CD160 mice did not show differences in disease compared to wild-type mice, BTLA LIGHT and CD160 LIGHT double knockout mice showed attenuated disease characterized by decreased clinical symptoms, increased retention of corneal sensitivity, and decreased infiltrating leukocytes in the cornea. We determined that the attenuation of disease in HVEM , BTLA LIGHT , and CD160 LIGHT mice correlated with a decrease in gamma interferon (IFN-γ)-producing CD4 T cells. Together, these results suggest that HVEM cosignaling through multiple binding partners induces a pathogenic Th1 response to promote HSK. This report provides new insight into the mechanism of HVEM in HSK pathogenesis and highlights the complexity of HVEM signaling in modulating the immune response following ocular HSV-1 infection. Herpes simplex virus 1 (HSV-1), a ubiquitous human pathogen, is capable of causing a progressive inflammatory ocular disease called herpes stromal keratitis (HSK). HSV-1 ocular infection leads to persistent inflammation in the cornea resulting in outcomes ranging from significant visual impairment to complete blindness. Our previous work showed that herpesvirus entry mediator (HVEM) promotes the symptoms of HSK independently of viral entry and that HVEM expression on CD45 cells correlates with increased infiltration of leukocytes into the cornea during the chronic inflammatory phase of the disease. Here, we elucidated the role of HVEM in the pathogenic Th1 response following ocular HSV-1 infection and the contribution of HVEM binding partners in HS