The long term goal of the studies that we propose is to understand molecular mechanisms involved in natural/innate response to viral infection. The Type I interferons are early inflammatory proteins, with a unique role in this response, since not only do they inhibit directly viral replication, they activate the immune system as well as stimulate TH1 development. However, the mechanisms by which virus induces expression of early inflammatory genes have not been clarified fully yet. We have identified two transcription factors, IRF-3 and IRF-7, that serve as direct transducers of virus mediated signaling from cytoplasm to nucleus. We have demonstrated also that, while IRF-3 is sufficient for the induction of IFNB genes in infected cells, IRF-7 is a master factor for the induction of IFNAs. Recently we have cloned another factor of the IRF family, IRF-5, and have shown that IRF-5 is also a transcription activator, the expression of which is limited to B cells, monocytes and dendritic cells. Furthermore, functional analyses have shown two very interesting features of IRF-5. Firstly, overexpression of IRF-5 may overlap or complement the ability of IRF-7 to activate IFNA genes in infected cells. Secondly, activation of IRF-5 and subsequent induction of IFNA genes has shown virus specificity. Therefore, the study proposed is focused on functional characterization of IRF-5 and its role in innate immunity. The proposal has three aims:
Aim 1. Functional characterization of IRF-5 and its role in infected cells;
Aim 2. Isolation and characterization of IRF-5 promoter in vitro and in vivo;
and Aim 3. Role of IRF-5 in activation and maturation of dendritic cells. Thus, the studies that we propose should contribute not only to the fundamental understanding of the modulation of cellular genes expression in infected cells and molecular basis of innate immunity, but also to provide a rational base for the design of novel therapeutic strategies for the treatment of the immune and inflammatory 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 |
| 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 |
