Type 1 IFN Function and Signaling in Immunity to Viruses

1 型干扰素在病毒免疫中的功能和信号传导

• 批准号: 7682782
• 负责人: CHRISTINE A. BIRON
• 金额: $ 39.75万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682782
• 关键词: Antigens; Antiviral Agents; Binding; Biochemical; Biological Process; CD8B1 gene; Dose; Exposure to; Gene Targeting; Genes; Health; Immune response; Immunity; Infection; Interferon Activation; Interferon Receptor; Interferon-alpha; Interferons; Lymphocytic choriomeningitis virus; Maps; Mediating; Molecular; Mus; Natural Killer Cells; Numbers; Pathway interactions; Production; Range; Receptor Signaling; Regulation; STAT protein; STAT1 gene; STAT1 protein; STAT2 gene; STAT4 gene; Shapes; Signal Pathway; Signal Transduction; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Virus; Virus Diseases; Work; cytokine; defined contribution; in vivo; insight; research study; response

The type 1 interferons (IFNs), including the IFNs alpha and beta, have potent antiviral effects, but also mediate a wide range of immunoregulatory functions. These include better-characterized effects on NK cells and incompletely understood effects on CD8 T cells. Some are paradoxical, and the mechanisms controlling type 1 IFN effects, to allow access to subsets when needed, are poorly characterized. The cytokines do stimulate a signaling pathway, depending on the signal transducers and activators of transcription (STAT) 1 and 2, to induce direct antiviral effects, but they can conditionally activate all of the STATs, including STAT4, and STAT4 contributes to IFN-? induction. As a result of experiments demonstrating that total STAT1 protein is dramatically induced at early times after infection, and that type 1 IFN activation of STAT4 negatively correlates with STAT1 levels, this project proposed to test the hypotheses that type 1 IFN effects 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. The work has proven the hypotheses to be correct. Unexpected mechanisms for the delivery of access to STAT1 as compared to STAT4 were discovered at the levels of differential expression of STAT4 and of apparent competition for binding to the type 1 IFN receptor, and these were shown to be important for health. Experiments are proposed in this renewal application to test the hypotheses that STATs act as master switches in promoting cellular responses by both enhancing and inhibiting type 1 IFN effects, and that the STAT1 and STAT4 effects on the reciprocal signaling pathway are influenced by, and have consequences for, other STAT molecules. This will be accomplished through four specific aims focusing on NK and CD8 T cell responses. Aim 1 will define the use of STATs as master switches to mediate positive and negative effects on responsiveness to type 1 IFNs. Aim 2 will mechanistically define the pathways regulating STAT levels. Aim 3 will broaden the characterization of type 1 IFN access to other STATs. Aim 4 will define the importance of modulating STAT levels and access for delivery of changing type 1 IFN biological functions during viral infection. Immunological, virological, biochemical, and molecular techniques will be used, and the work will be advanced by studies of responses ex vivo following exposure to cytokines, and in vivo following lymphocytic choriomeningitis virus infections in wild type and genetically altered mice. The project promises to continue to advance understanding of the control of type 1 IFN effects in shaping immune responses to infection, and to provide insights for use of cytokines in therapeutic applications. Even more broadly, however, it will identify paradigms for how cytokine effects are regulated to add value to a limited number of genes.

1 型干扰素 (IFN)，包括 IFN α 和 β，具有有效的抗病毒作用，但也 介导广泛的免疫调节功能。其中包括对以下方面的更好表征的影响： NK 细胞和对 CD8 T 细胞的影响尚不完全清楚。有些是自相矛盾的， 控制 1 型干扰素效应（以允许在需要时访问子集）的机制很差 特点。细胞因子确实会刺激信号传导途径，具体取决于信号转导器 以及转录激活剂 (STAT) 1 和 2，以诱导直接抗病毒作用，但它们可以 有条件地激活所有 STAT，包括 STAT4，而 STAT4 有助于 IFN-α就职。 实验结果表明，总 STAT1 蛋白在早期就被显着诱导。 感染后数次，并且 STAT4 的 1 型 IFN 激活与 STAT1 水平呈负相关， 该项目旨在测试 1 型干扰素效应是通过调节来控制的假设 进入不同的细胞内信号传导途径，并且这种调节是必需的和传递的 在对病毒感染的先天和适应性免疫反应期间。工作证明了 假设是正确的。相比之下，访问 STAT1 的意外机制 在 STAT4 的差异表达水平和表观 与 1 型干扰素受体结合的竞争，这些都被证明对健康很重要。 在此更新应用中提出了实验来测试 STAT 作为主控的假设 通过增强和抑制 1 型 IFN 效应来促进细胞反应的开关，并且 STAT1 和 STAT4 对相互信号传导通路的影响受到并具有 对其他 STAT 分子的影响。这将通过四个具体目标来实现 重点关注 NK 和 CD8 T 细胞反应。目标 1 将定义使用 STAT 作为主开关 介导对 1 型干扰素反应的积极和消极影响。目标2将机械地 定义调节 STAT 水平的途径。目标 3 将拓宽 1 型干扰素的表征 访问其他统计数据。目标 4 将定义调节 STAT 水平和访问的重要性 在病毒感染期间传递改变的 1 型干扰素生物学功能。免疫学、病毒学、 将使用生物化学和分子技术，并通过研究来推进这项工作 暴露于细胞因子后的离体反应，以及淋巴细胞性脉络膜脑膜炎后的体内反应 野生型和基因改造小鼠的病毒感染。该项目承诺将继续推进 了解 1 型干扰素在塑造针对感染的免疫反应中的作用的控制，以及 为细胞因子在治疗应用中的使用提供见解。然而，更广泛地说，它将 确定如何调节细胞因子效应以增加有限数量基因的价值的范例。