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Abstract
Herpes simplex virus type-1 (HSV-1) is a ubiquitous and medically significant component of the human virome. The ability of HSV-1 to establish lifelong latent infections, the lack of a vaccine, and the inability of therapeutics to eliminate the virus means that most humans live with HSV-1. While often benign, HSV-1 is the leading cause of viral encephalitis worldwide and infectious corneal blindness in developed countries. Vertically transmitted HSV-1 has especially dire consequences for newborns. These diseases are a direct result of HSV-1 infecting immune privileged sites, the cornea and the nervous system. Relative to other sites, these organs are more tolerant of new antigens, which do not elicit a canonical inflammatory response. Thus, this thesis examines the immunological consequences of HSV-1 infection and immunity in these immune privileged sites.
In Chapter 2, we elucidate a new immune pathway that contributes to herpetic stromal keratitis (HSK), an inflammatory ocular disease initiated by HSV-1. Using the mouse model, we found that autophagy in dendritic cells significantly contributed to HSK disease by specifically enhancing T cell activation and pathological corneal inflammation. This work broadens our understanding of the immunopathology that drives HSK and implicates autophagy as a new therapeutic target. In Chapter 3, we examine the role of humoral immunity in neural tissue after HSV-1 infection. Using mouse and human tissue, we discovered that antibodies can readily access naive neural tissue, even in the fetus and neonate. Thus, antiviral maternal antibodies significantly prevent HSV-1 neurological infection and death in neonatal mice. These results reveal a novel role of maternal antibodies to mediate neuroprotection in newborns. In Chapter 4, we investigate the potential consequences of HSV-induced neuroimmunology. Using the mouse model, we detected immune receptors and chronic inflammatory signatures in the nervous system after HSV-1 infection. However, we did not find that these immune factors impacted neuronal signaling or inflammatory neurodegenerative disease. Overall, this dissertation underscores the significant immunological changes accompanying HSV-1 infection in the cornea and nervous system. Given the remarkable ubiquity and persistence in the human population, HSV-1 challenges the notion of immune privilege in both the literal and conceptual sense.
