The long-term goal of our studies is to delineate the changes in cell physiology induced by viral infection and to dissect the molecular mechanisms by which virus modulates the expression of cellular genes. We have shown during the current funding period that two transcription factors of the IRF family, IRF-3 and IRF-7, function as direct transducers of virus-induced signaling and play a critical role in the activation of several cytokine and chemokine genes. We have shown that IRF-7 functions as a master factor for the induction of IFNA genes (IFNAs) and plays a critical role in the induction of IFNAs in infected cells. Recently we have cloned IRF-5 cDNA from dendritic cells and initiated functional characterization of IRF-5 that has not been previously studied. We have found that the expression of IRF-5 is restricted to dendritic cells and B cells and when over-expressed, it can functionally replace or complement IRF-7. Despite the functional similarity between IRF-5 and IRF-7, the function of IRF-5 is not redundant since IRF-5 shows several unique features. Most notably (1) The activation of IRF- 5 by phosphorylation is virus specific, (2) IRF-5 induces IFNA genes distinct from those induced by IRF-7 and (3) Activated IRF-5 stimulates expression of a set of C-C chemokines. Thus, our data indicate that IRF-5, in cell type and virus-specific manner, cooperates or replaces IRF-7 function in the activation of IFN genes. ? ? We propose that IRF-3, IRF-5 and IRF-7, all of which serve as direct transducers of virus-mediated signaling and activate expression of cytokine and chemokine genes, may serve as novel targets for therapeutic intervention of viral infections as well as pathogenic inflammatory and autoimmune responses.
| 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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