Biology and Biomedical Sciences: Immunology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
The type I interferon: IFN) cascade is critical in control of herpes simplex virus type I: HSV-1) infection and relies on specific recognition molecules to rapidly signal viral infection via interferon regulatory factor-3: IRF-3) -dependent pathways. The absence of these recognition molecules or the loss of IRF-3 would be predicted to render early recognition pathways inoperative and thus impact viral infection. However, previous results had produced contradictory results in terms of the role of IRF-3 during HSV-1 infection. In this study, infected IRF-3-/- immune cells were found to support increased HSV-1 replication compared to control cells. In addition, IRF-3 deficient cells exhibited delayed type I IFN synthesis following infection and were partially restored in the presence of exogenous IFN; blockade of the type I IFN receptor resulted in similar titers in control and IRF-3-/- cells. Together, the data demonstrated that defective and deficient type I IFN production in IRF-3-/- cells resulted in increased HSV-1 replication in vitro. In vivo, IRF-3 deficiency was found to have no significant impact on HSV-1 replication in peripheral tissues following ocular challenge with a laboratory: 17) or a neurovirulent strain: McKrae) of virus. However, IRF-3-/- mice were significantly more susceptible to central nervous system infection following both peripheral and intracranial infection with HSV-1. Increased viral replication and inflammatory cytokine production were observed in brain tissues of IRF-3-/- mice compared to control mice. In addition, the production of IFNβ and IFNα was delayed and reduced in IRF-3-/- brains. These data demonstrate a critical role for IRF-3 in control of central nervous system infection following HSV-1 challenge. Together, the data illustrate the importance of IRF-3 mediated pathways in initiating the type I IFN cascade necessary to control HSV-1 infection both in vitro and in vivo.
Menachery, Vineet, "The Impact Of Interferon Regulatory Factor 3 On The Immune Response To Herpes Simplex Virus Type I Infection" (2010). All Theses and Dissertations (ETDs). 240.