Visualizing Interferon-beta Induction In Vivo

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DESCRIPTION (provided by applicant): Virus infection of vertebrates triggers multiple host defense mechanisms, and type I interferons (IFNs) are among the earliest of these. Type I (or 1 and 2) IFNs are best known for their antiviral functions. IFN-1/2 synthesis is induced by virus infection of all cell types. When neighboring cells are exposed to secreted IFN-1/2, the binding of these ligands to the IFN-1/2 receptor leads to the transcriptional upregulation of the many interferon-stimulated genes which mediate the anti-viral state. This very early innate immune response to viral invasion is very important for limiting viral replication and spread. But while the type I IFN response can contain a virus infection, an antigen- specific T cell response is needed for resolution. Recent progress in the area of IFN gene regulation and function has led to the realization that, in addition to their antiviral effects, IFN-1/2 also have a role in promoting an effective and appropriate adaptive immune response to viral infection. IFN-2 and IFN-1 secreted from infected cells and plasmacytoid dendritic cells can also promote antigen presentation, lymphocyte activation, and lymphocyte survival. As type I IFNs have such an important role in anti-viral defense, it is not surprising that all viruses studied have found ways of inhibiting IFN-1/2 production and or action. These mechanisms vary among pathogens, and their effectiveness can influence viral virulence, chronicity, and ability to reinfect. Our laboratory is interested in how different respiratory viruses induce type I IFNs in vivo, and how production of these cytokines affects the development of virus specific lymphocyte responses. Our ability to study these dynamic processes would be markedly enhanced if we were able to trace the source and timing of IFN production during an active infection. This application describes our plans to derive indicator mice carrying a gene for green or red fluorescent protein that is driven by a type I IFN promoter. These reagents will allow virologists to study the ability of many different viruses to activate and/or suppress type I IFN production in vivo and in vitro. PUBLIC HEALTH RELEVANCE Virus infection triggers multiple host defense mechanisms, and the cytokines called type I interferons (IFNs) are among the earliest of these. This very early innate immune response to viral invasion is important for limiting viral replication and spread. As type I IFNs have such an important role in anti-viral defense, it is not surprising that all viruses studied have found ways of inhibiting IFN production and or action. This application describes our plan to derive indicator cell lines and transgenic mice that will fluoresce when the IFN genes are activated. These reagents will allow virologists to study the ability of many different viruses to activate and/or suppress type I IFN production in vivo and in vitro.