Immunomodulatory Receptors in Herpes Simplex Virus Pathogenesis


Herpes simplex virus (HSV) is a ubiquitous human pathogen capable of causing debilitating diseases such as herpes stromal keratitis (HSK) and herpes simplex encephalitis (HSE). Although HSV infection initiates disease pathogenesis, the resulting clinical manifestations are attributed to immunopathological events that occur following viral clearance. To elucidate the molecular mechanisms that promote HSK and HSE, I investigated the role of immunomodulatory receptors that mediate the immune response to HSV-1 infection.Herpesvirus entry mediator (HVEM) is a host protein that interacts with its binding partners, LIGHT, BTLA, and CD160 to deliver stimulatory or inhibitory signals to various leukocytes. Although originally discovered as a viral entry receptor, previous studies highlighted the entry receptor independent immunomodulatory role of HVEM as a major contributor of uncontrolled inflammation following ocular HSV-1 infection. HSK is an HSV-1 induced ocular disease characterized by T cell mediated leukocyte infiltration that leads to corneal opacity and loss of corneal sensitivity. My research focused on how HVEM-binding partner interaction influences overall HSK pathogenesis by altering immune mediated events following infection. In a murine model of ocular HSV-1 infection, I found that HVEM binding partners had a differential role in promoting disease. Mice lacking in multiple binding partners, BTLA-/-LIGHT-/- and CD160-/-LIGHT-/- mice showed significantly attenuated clinical symptoms, improved corneal sensitivity, and reduced infiltration of leukocytes compared to wildtype (WT) mice suggesting that multiple HVEM-binding partner interactions contribute to HSK pathogenesis. Additionally, I found that HVEM and multiple binding partners promote the pathogenic T cell response that drives the chronic inflammatory phase of HSK. I observed significantly reduced T cell activation and levels of Th1 cells in draining lymph nodes of HVEM, BTLA-/-LIGHT-/-, and CD160-/-LIGHT-/- mice compared to WT mice following infection. My findings reveal an important contribution of HVEM and its binding partners in promoting HSK pathogenesis by upregulating the pathogenic T cell response. I next focused on elucidating the mechanisms that mediate HSE pathogenesis. HSE is characterized by inflammation in the brain parenchyma caused by HSV-1 infection in the brain. Prolonged immune activation causes neuronal damage leading to long term neurologic sequelae in majority of the affected individuals. I investigated the role of TAM receptors, receptor tyrosine kinases that mediate components of the immune response, in HSE pathogenesis. TAM receptors control the type I interferon (IFN-I) response by downregulating IFN-a/b receptor (IFNAR) signaling, an innate immune pathway necessary for viral clearance. They are also known to be key regulators in facilitating phagocytic clearance of apoptotic cells. I found that the TAM receptor MerTK provided protection against mortality in a murine model of HSE by ameliorating neuroinflammation. MerTK not only contributed to controlling the inflammatory response triggered by IFNAR signaling, it reduced the number of apoptotic cells in the brain following infection, preventing unnecessary immune activation caused by the presence of apoptotic debris. I also observed increased leukocyte infiltration in the brain in mice lacking MerTK (Mertk-/-), further indicating that the mechanisms of MerTK downregulate the inflammatory immune response. These data provide insight into the critical role of TAM receptors in mediating neuroinflammation, suggesting their potential involvement in controlling long term neurologic sequelae in HSE.

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