Efficacy and immunological mechanisms of type 1 interferon gene therapy in murine cytomegalovirus
Year: 2002
Type: dissertation
Abstract: This thesis presents a comparative analysis of the type I Interferon (IFN) subtypes and an evaluation of their potential as DNA vaccines in a model of murine cytomegalovirus (MCMV) infection and disease.MCMV induces acute and chronic phases of myocarditis, a heart disease characterised by an inflammatory cell infiltrate, in susceptible BALB/c mice.The type I IFNs comprise 14 IFNα genes in the human and >10 IFNα genes in the mouse with a single IFNβ gene in both species, however, the purpose of their multiplicity has remained unclear to date.An extensive panel of murine type I IFN subtype genes, including IFNA1, A2, A4, A5, A6, A9 and B, were sub-cloned into the mammalian expression vector pkCMVint (Vical, Inc.) for expression in BALB/c mice.These DNA constructs express biologically active IFN both in vitro and in vivo with systemic, low level expression persisting in the mouse for up to 4 weeks.The individual type I IFN subtypes differentially affect the immune response to MCMV challenge.IFNA6 proved most efficacious, reducing viral replication and inflammation in the acute and chronic phase of disease.Data suggests this occurs via induction of a Th1-like cytokine and antibody response.Furthermore, IFNA6 inoculation after the acute phase was shown to protect mice from the onset of chronic myocarditis.Characterisation of the immune cell response in IFN-treated, MCMV-infected mice demonstrated that type I IFN subtypes modulate the type of immune cells infiltrating the myocardium during myocarditis.Notably, reduced CD8+ and CD4+ T cells and B cell numbers in the heart was associated with reduced chronic myocarditis.Finally, coadministration of type I IFNs, in particular, IFNA6 and IFNB, synergistically improved immunotherapy against MCMV infection and myocarditis.The findings detailed here highlight the potential for the type I IFNs as DNA vaccines and most importantly, demonstrate that the type I IFNs have differential antiviral and immunomodulatory efficacies in the MCMV model of infection and myocarditis.
Author: Emmalene J. Bartlett
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W103613331