Type 1 IFN Function and Signaling in Immunity to Viruses

描述（由申请人提供）：先天细胞因子，1型干扰素（IFN），包括干扰素α和β，首先通过其抗病毒功能被发现。现在知道它们还介导广泛的免疫调节作用。其中某些是矛盾的，并且控制ifn - α / β暴露后诱导的效应子集的机制仍有待阐明。同样地，CD8 T细胞的调控也不完全清楚，但在病毒感染期间观察到显著的CD8 T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IFN的作用是由不同细胞内信号通路的调节控制的，并且这种调节是对病毒感染的先天和适应性免疫反应所必需和传递的。因此，这些假设呈现了一幅“1型干扰素作为病毒感染的先天免疫反应和适应性免疫反应之间的联系”的图景。基于我们对淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染和细胞因子治疗后信号转导和转录激活因子（STAT1）和STAT4功能的研究，我们提出STAT1的调控是1型IFN暴露后转换成不同反应的关键机制。计划实验的重点将是对诱导抗病毒状态，ifn - α / β扩增和CD8 T细胞ifn - γ产生和增殖反应的影响。这项工作将在三个具体目标下完成。目的1将评估感染诱导的1型IFN对靶基因表达的影响。目的2将定义STAT在形成由1型ifn介导的生物效应的途径中的功能。这个目标将解决STATs的下游后果。目标3将从机制上推进对STATs如何被监管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，因此它们的结果很可能导致发现仅靠体外研究无法预测的新途径。它们将有助于了解促进抵抗感染的因素，特别是先天免疫成分。它们还有望为感染、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防备和防御生物恐怖主义的计划。

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.