Visualizing Interferon-beta Induction In Vivo

描述(申请人提供)：脊椎动物的病毒感染触发多种宿主防御机制，I型干扰素(IFN)是其中最早的一种。I型(或1类和2类)干扰素以其抗病毒功能而闻名。干扰素-1/2的合成是由所有细胞类型的病毒感染诱导的。当邻近细胞暴露于分泌的干扰素-1/2时，这些配体与干扰素-1/2受体的结合导致许多干扰素刺激的基因转录上调，这些基因介导了抗病毒状态。这种对病毒入侵的非常早期的先天免疫反应对于限制病毒的复制和传播非常重要。但是，虽然I型干扰素反应可以包含病毒感染，但需要抗原特异性T细胞反应才能解决。在干扰素基因调控和功能方面的最新进展使人们认识到，除了抗病毒作用外，干扰素-1/2还在促进对病毒感染的有效和适当的适应性免疫反应中发挥作用。感染细胞和浆细胞样树突状细胞分泌的干扰素-2和干扰素-1也能促进抗原提呈、淋巴细胞活化和淋巴细胞存活。由于I型干扰素在抗病毒防御中具有如此重要的作用，所有研究的病毒都找到了抑制干扰素-1/2的产生和/或作用的方法也就不足为奇了。这些机制因病原体的不同而不同，它们的有效性可以影响病毒的毒力、慢性化和再感染能力。我们的实验室感兴趣的是不同的呼吸道病毒如何在体内诱导I型IFN，以及这些细胞因子的产生如何影响病毒特异性淋巴细胞反应的发展。如果我们能够追踪活动性感染期间干扰素产生的来源和时间，我们研究这些动态过程的能力将显著增强。这项申请描述了我们的计划，即获得携带绿色或红色荧光蛋白基因的指示性小鼠，该基因由I型干扰素启动子驱动。这些试剂将使病毒学家能够研究许多不同病毒在体内和体外激活和/或抑制I型干扰素产生的能力。与公共卫生相关的病毒感染触发多种宿主防御机制，被称为I型干扰素(IFN)的细胞因子是其中最早的一种。这种对病毒入侵的非常早期的先天免疫反应对于限制病毒的复制和传播非常重要。由于I型干扰素在抗病毒防御中具有如此重要的作用，因此所有研究的病毒都找到了抑制干扰素产生和/或作用的方法也就不足为奇了。这项申请描述了我们的计划，即获得指示细胞系和转基因小鼠，当干扰素基因被激活时，它们将发出荧光。这些试剂将使病毒学家能够研究许多不同病毒在体内和体外激活和/或抑制I型干扰素产生的能力。

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.