Type 1 IFN Function and Signaling in Immunity to Viruses

描述(申请人提供)：先天的细胞因子，1型干扰素(干扰素)，包括干扰素α和β，首先通过它们的抗病毒功能进行鉴定。现在已经知道，它们还调节一系列广泛的免疫调节效应。其中某些是自相矛盾的，控制暴露于IFNα/β后所产生的效应子集的机制仍有待阐明。同样，CD8T细胞的调节还不完全清楚，但在病毒感染时观察到戏剧性的CD8T细胞反应，引起高浓度的1型IFN。该项目将测试主要假设，即1型干扰素的作用是由不同细胞内信号通路的调节控制的，并且这种调节是病毒感染的先天和获得性免疫反应所必需的和传递的。因此，这些假说描绘了一幅“1型干扰素作为病毒感染的先天免疫反应和获得性免疫反应之间的纽带”的图景。根据我们对淋巴细胞脉络膜脑膜炎病毒(LCMV)感染和细胞因子治疗后信号转导和转录激活因子(STAT)1和STAT4功能的研究，STAT1的调节被认为是1型干扰素暴露后切换到不同反应的关键机制。计划中的实验的重点将放在诱导抗病毒状态、干扰素-α/β扩增以及CD8T细胞干扰素-伽马的产生和增殖反应上。这项工作将按三个具体目标完成。目的1评价感染诱导的1型干扰素对靶基因表达的影响。目标2将定义STAT在塑造1型IFN介导的生物效应的途径中的作用。这一目标将解决统计数据下游的后果。目标3将从机械上促进对如何监管统计数据以促进特定效果的理解。由于这些研究是由体内生物学的特征驱动的，他们的结果可能会导致发现仅靠体外研究无法预测的新途径。它们将有助于理解促进对感染的抵抗力的因素，特别是天然免疫成分。他们还承诺为治疗感染、癌症和免疫缺陷的治疗干预方法提供见解。从这项工作中获得的信息将有助于制定针对生物恐怖主义的准备和防御计划。

DESCRIPTION (provided by applicant): The innate cytokines, type 1 interferons (IFN), including interferons alpha and beta, were first identified by their anitiviral functions. It is now know that they also mediate a wide range of immunoregulatory effects. Certain of these are paradoxical, and mechanisms controlling the subset of effects induced following IFNalpha/ beta exposure remain to be elucidated. Likewise, CD8 T cell regulation is incompletely understood, but dramatic CD8 T cell responses are observed during viral infections eliciting high concentrations of type 1 IFNs. This project will test the primary hypotheses that the type 1 IFN effects elicited are controlled by regulation of access to different intracellular signaling pathways, and that this regulation is required and delivered during innate and adaptive immune responses to viral infections. Thus, these hypotheses present a picture of "Type 1 Interferons as Links Between Innate and Adaptive Immune Responses to Viral Infections". Based on our studies of functions for signal transducers and activators of transcription (STAT) 1 and STAT4 following infections with lymphocytic choriomeningitis virus (LCMV) and treatments with cytokines, regulation of STAT1 is proposed to be a critical mechanism for switching to different responses following type 1 IFN exposure. Focus of the planned experiments will be on effects for induction of antiviral state, IFN-alpha/beta amplification, and the CD8 T cell IFN-gamma production and proliferative responses. The work will be accomplished in three specific aims. Aim 1 will evaluate the infection-induced changes in type 1 IFN effects for target gene expression. Aim 2 will define STAT functions in pathways shaping the biological effects mediated by type 1 IFNs. This aim will address consequences downstream of STATs. Aim 3 will mechnistically advance understanding of how the STATs are regulated to promote particular effects. As these studies are driven by characterization of in vivo biology, their results are likely to lead to discovery of novel pathways not predicted by in vitro studies alone. They will contribute to the understanding of the factors, particularly the innate immune components, promoting resistance to infections. They also promise to provide insights for approaches to therapeutic intervention in the treatment of infections, cancers, and immunodeficiencies. The information derived from this work will help in devising plans for readiness and defense against bio-terrorism.