Gerald Alter (Committee Member), Scott Baird (Committee Chair), Nancy Bigley (Advisor), Barbara Hull (Committee Member), Peter Lauf (Committee Member)
Doctor of Philosophy (PhD)
Epidermal cells such as keratinocytes are the major site of Herpes Simplex Virus Type 1 (HSV-1) replication in active primary or recurring herpes infection. In this study, a murine keratinocyte cell line (HEL-30) was shown to be refractory to IFNγ induction of an antiviral state to HSV-1 infection, while IFNγ did induce an antiviral state in a murine fibroblast cell line (L929). Particularly, IFN-gamma and its peptide mimetic protected fibrobasts from viral-induced cytopathic effect while the keratinocytes were destroyed by the infection. Suppressor of cytokine synthesis-1 (SOCS-1) a negative regulator of IFNγ, was hypothesized to be responsible for the refractiveness of HEL-30 cells to IFNγ treatment. In contrast to negligible expression in the fibroblasts, HSV-1 caused the keratinocytes to express 4-fold higher levels of SOCS-1 mRNA. SOCS-1 protein was also elevated in HSV-1-infected HEL-30 cells. In agreement with these observations, activation of STAT-1α, a key protein involved in IFNγ signaling, was inhibited in HSV-1-infected HEL-30 cells while not affected in L929 cells. Additionally, HSV-1-infected HEL-30 cells showed increased activity at the SOCS-1 promoter in a luciferase assay.Keratinocytes were responsive to the antiviral action of IFN-gamma and protected from lysis by pretreatment with either a peptide antagonist of SOCS-1or SOCS-1 small interfering RNA. An interferon-sensitive mutant of HSV-1 (dl1403) was sensitive to IFNγ treatment in HEL-30 cells. HSV-1 dl1403 also induced only moderate activity at the SOCS-1 promoter as compared to wild-type virus. These results suggest a role for regulation of SOCS-1 in treatment of HSV-1-induced cytopathology. Further, the actions of the SOCS-1 peptide antagonist have implications for regulation of immune responses in a number of diseases from cancer to auto-immune disorders.
Department or Program
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