Characterization of Sex Differences in Ocular Herpes Simplex Virus 1 Infection and Herpes Stromal Keratitis Pathogenesis of Wild-Type and Herpesvirus Entry Mediator Knockout Mice

Abstract

Sex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice. Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050–1059, 2012, https://doi.org/10.1002/bies.201200099 ). Herpes simplex virus 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune-privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, et al., Prog Retin Eye Res 32:88–101, 2013, https://doi.org/10.1016/j.preteyeres.2012.08.002 ). Our research focuses on the role of herpesvirus entry mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM knockout [KO] mice) exhibit lower levels of immune cell infiltrates and less severe ocular disease in the cornea than wild-type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested whether sex acts as a biological variable in the immune response to HSV-1 infection and herpes stromal keratitis (HSK) pathogenesis. Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers were determined, and immune cell infiltrates were collected and analyzed. Our results indicated no significant differences in viral titers in tear film or affected tissues, in immune cell infiltration, or in clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model and that male and female mice of the C57BL/6 background can be used similarly in studies of ocular HSV-1 pathogenesis. IMPORTANCE Sex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice.