Interferon regulatory factor 3 (IRF3) plays an important role in activating the innate immune response in a variety of conditions, including viral infection. As well as regulating the immune response to viruses, IRF3 is involved in regulating cellular functions including apoptosis. Apoptosis and the inflammatory response to viral infection are very different; therefore, it is obvious that IRF3 plays dramatically different roles in the cell depending on the conditions. We previously identified a non-activating phosphorylation of IRF3 in response to adenovirus (Ad) in which Serine-173 is phosphorylated. In addition to Ad infection, IRF3- S173 is phosphorylated in response to genotoxic stresses including ultraviolet (UV) irradiation and etoposide. In this study, I show that this phosphorylation event is involved in a variety of processes including protein stability, cell survival and IRF3 regulation. Thus, phosphorylation of IRF3-S173 is a novel and important event in a complex regulatory pathway of an integral protein.

Biological DNA Sensor defines the meaning of DNA sensing pathways and demonstrates the importance of the innate immune responses induced by double stranded DNA (dsDNA) through its influencing functions in disease pathology and immune activity of adjuvants for vaccines. Though discussed in specific subsections of existing books, dsDNA and its immunogenic properties has never received the complete treatment given in this book. Biological DNA Sensor approaches the impact of dsDNA's immunogenicity on disease and vaccinology holistically. It paints a complete and concise picture on the topic so you can understand this area of study and make more informed choices for your respective research needs. Chapters are authored by researchers who are renowned for their research focus, ensuring that this book provides the most complete views on the topics. - Multi-authored by a distinguished panel of world-class experts - Ideal source of information for those wanting to learn about DNA sensing - Provides in-depth explanations of DNA sensing pathways and the innate immune system, bridging the gap between them

Interferon regulatory factor 3 (IRF3) is a transcription factor found in the cytoplasm of most nucleated cells. Upon pathogen detection by pattern recognition receptors, IRF3 becomes activated and translocates to the nucleus where it mediates the production of type I interferon (IFN) and IFN-stimulated genes. The collective actions of these genes induce an antimicrobial state within infected and neighboring cells, allowing for pathogen clearance. Whereas the type I IFN system has been studied extensively in the context of pathogen responses, it has more recently become appreciated for its role in immune cell modulation. In this report we discuss novel findings highlighting the involvement of the type I IFN system--with a focus on IRF3--in T cell development, activation, differentiation, and cytokine production. Using a combination of in vitro assays and in vivo disease models, we demonstrate that IRF3 is a positive regulator of lL-17 and IFN-[gamma] in CD4+ T cells. We show that IRF3-deficient CD4+ T cells have impaired production of the pro-inflammatory cytokines IL-17 and IFN-[gamma], and are unable to induce disease in the T cell transfer model of colitis. Unexpectedly, we observed IRF3 nuclear translocation in activated T cells. To our knowledge, this is the first description of IRF3 activation following T cell receptor stimulation. These results, which are the focus of chapter 1, reveal a previously unappreciated role for IRF3 in CD4+ T cell responses and extend its role beyond the innate immune response to pathogens. Additionally, we show that type I IFN limits T cell production of IL-2--a cytokine required for T cell activation and expansion--by indirectly altering histone modifications in the IL-2 promoter to retain the locus in an inaccessible configuration. These results, which are the focus of chapter 2, help explain why type I IFN has been an effective treatment for multiple sclerosis--a T cell-mediated autoimmune condition.

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Interferon regulatory factor 3 (IRF-3) plays a critical role in the host cell response to both bacterial and viral infection. IRF-3 is activated by Toll-like receptors (TLRs) and cytoplasmic nucleic acid sensors, and serves to upregulate interferon beta and interferon stimulated genes (ISGs), thereby providing a quick and effective response to infection. In this work, two novel mechanisms of regulation in the IRF-3 pathway are revealed. The first part of this thesis work shows that upon binding to lipopolysaccharide, TLR-4 signaling activates phospholipase C gamma 2 (PLCg2), which cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) into Inositol 1,4,5-triphosphate (IP3) and regulates IP3R activity. Inositol 1,4,5-triphosphate receptors (IP3Rs) mediate the release of calcium from the endoplasmic reticulum into the cytosol. The hypothesis presented here is that, upon calcium release, the calcium-dependent phosphatase calcineurin becomes activated and activates dynamin-dependent endocytosis of the LPS-TLR4 complex. Signaling occurs from the early endosomes via the TRAM-TRIF pathway, and induces the IRF3-dependent gene response. Our results suggest a novel means by which the IRF3 pathway is regulated. The second part of this thesis work describes the Schlafen (Slfn) gene family and its complex role in the immune response. The family is comprised of nine murine members, which are divided into short (Slfn 1 and 2), medium (Slfn 3 and 4) and long (Slfn 5, 8, 9, 10,14) subtypes. The short subtype member, Slfn2, is a cytoplasmic protein that binds to foreign nucleic acids and inhibits protein translation, putatively as a host defense strategy. However, short and medium subtypes, Slfn2 and Slfn3, appear to inhibit Interferon stimulated gene (ISG) production via the IRF3 pathway, thus indicating a role in attenuating the immune response. Moreover, Slfn8, a long subtype member, does not appear to have any effect on ISG induction, indicating divergent roles of different individual Slfn family members. We propose that the Slfn family is differentially regulated during a response to infection, thus initially mediating cellular defense and, later, downregulation of response through the varying participation of individual Slfn proteins within a complex.

This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.