Abstract
Infection with herpes simplex virus type 1 (HSV-1) and HSV-2 is initiated by viral glycoprotein D (gD) binding to a receptor on the host cell. Two receptors, herpesvirus entry mediator (HVEM) and nectin-1, mediate entry in murine models of HSV-1 and HSV-2. HVEM is dispensable for HSV-2 infection of the vagina and brain, but is required for WT pathogenesis of HSV-1 infection of the cornea. By challenging WT and HVEM KO mice with multiple strains of HSV-1 and HSV-2, we demonstrate that without HVEM, all HSV-1 strains tested do not replicate well in the cornea and infection does not result in severe symptoms, as observed in WT mice. In contrast, all HSV-2 strains tested had no requirement for HVEM to replicate to WT levels in the cornea and still cause severe disease. These findings imply that HSV-2 does not require HVEM to cause disease regardless of route of entry, but HVEM must be present for HSV-1 to cause full pathogenesis in the eye. These findings uncover a unique role for HVEM in mediating HSV-1 infection in an area innervated by the trigeminal ganglion and may explain why the presence of HVEM can lead to severe inflammation in the cornea. Thus, the dependence on HVEM is a dividing point between HSV-1 and HSV-2 that evolved to infect areas innervated by different sensory ganglia.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 20649-20654 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 109 |
| Issue number | 50 |
| DOIs | |
| State | Published - Dec 11 2012 |
Funding
ACKNOWLEDGMENTS. We thank members of the R.L. laboratory for their help and support, specifically Nan Susmarski for expert cell culture preparation. This work was funded by Public Health Service Grant R21 EY021306 (to R.L.) from the National Eye Institute and Northwestern University Clinical and Translational Sciences Institute (A.H.K.), and the Infectious Disease Society of America Medical Scholars Program (A.H.K.). Ethics Statement. This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Northwestern University (Protocol Number: 2012–1728). Where noted, all procedures were performed under ketamine/xylazine anesthesia and every effort was made to minimize suffering.
Keywords
- Eye infection
- Herpes stromal keratitis
- Viral eye disease
- Viral pathogenesis
ASJC Scopus subject areas
- General