The long term objective of this study is to determine the biological role of the interferon system in virus infection and virus-induced neoplasia by using mice as a model system. Clusters of four mouse alpha interferon genes were cloned and characterized and alpha and beta interferon genes were localized to chromosome 4, between the Mup and brown locus. These genes are expressed in infected mouse cells and code for biologically active interferons in Escherichi coli. The present proposal focuses on: 1.) Characterization of the remaining eight alpha interferon genes identified in the genomic library and determination of whether they are part of the previously identified cluster; using the recombinant strains and mice congenic for specific loci, precise mapping of the localization of alpha and beta interferon genes on the mouse chromosome 4 in relation to the other known markers. 2.) Analysis of the molecular nature of gene polymorphism and expression and inducibility of the polymorphic genes. 3.) The role of a poly G cluster, identified in the promoter region of one of the alpha interferon genes, in inducibility and expression. 4.) Effect of mouse genotype, tissue and inducer on the expression of alpha and beta interferon genes in vivo (using probes specific for each alpha and beta interferon gene cloned) and the role of interferon in genetic resistance of certain strains of mice to viral infection. 5.) Analysis of the role of endogenous interferon in retrovirus replication and induced neoplasia. These studies will clarify the role of interferon in viral infection and neoplasia and establish the genetic variability in the interferon system. The data obtained should help to our understanding of the role of interferon in virus infection in man and provide a more rational basis for therapeutic application of interferon in man.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Virology Study Section (EVR)
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Johns Hopkins University
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Okumura, Atsushi; Pitha, Paula M; Yoshimura, Akihiko et al. (2010) Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J Virol 84:27-33
Harty, Ronald N; Pitha, Paula M; Okumura, Atsushi (2009) Antiviral activity of innate immune protein ISG15. J Innate Immun 1:397-404
Okumura, Atsushi; Pitha, Paula M; Harty, Ronald N (2008) ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc Natl Acad Sci U S A 105:3974-9
Paun, A; Pitha, P M (2007) The IRF family, revisited. Biochimie 89:744-53
Pitha, P M; Kunzi, M S (2007) Type I interferon: the ever unfolding story. Curr Top Microbiol Immunol 316:41-70
Pitha-Rowe, Ian F; Pitha, Paula M (2007) Viral defense, carcinogenesis and ISG15: novel roles for an old ISG. Cytokine Growth Factor Rev 18:409-17
Barnes, Betsy J; Field, Ann E; Pitha-Rowe, Paula M (2003) Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes. J Biol Chem 278:16630-41
Barnes, Betsy J; Kellum, Merrill J; Pinder, Karen E et al. (2003) Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res 63:6424-31
Izaguirre, Alexander; Barnes, Betsy J; Amrute, Sheela et al. (2003) Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol 74:1125-38
Barnes, Betsy; Lubyova, Barbora; Pitha, Paula M (2002) On the role of IRF in host defense. J Interferon Cytokine Res 22:59-71

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