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IFNα和β，具有强大的抗病毒作用，但也 调节广泛的免疫调节功能。这些包括更具特征性的影响 NK细胞和对CD8T细胞的作用还不完全清楚。有些是自相矛盾的，而 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 特色化的。细胞因子确实会刺激信号通路，这取决于信号转导。 和转录激活因子(STAT)1和2，以诱导直接的抗病毒作用，但它们可以 有条件地激活所有的统计数据，包括STAT4，STAT4有助于干扰素？？归纳法。 由于实验表明，总的STAT1蛋白在早期被显著诱导 STAT4的1型干扰素活性与STAT1水平呈负相关， 该项目旨在验证1型干扰素效应受调控的假说。 获得不同的细胞内信号通路，并且这一调节是必需的并被提供 在对病毒感染的先天和获得性免疫反应过程中。这项工作证明了 假设是正确的。与之相比，提供对STAT1的访问的意外机制 TO STAT4在STAT4的差异表达水平和表观表达水平上被发现 竞争与1型干扰素受体的结合，这些被证明对健康很重要。 在这个更新的应用程序中提出了一些实验，以检验统计数据充当主控的假设 通过增强和抑制1型干扰素效应来促进细胞反应的开关，以及 STAT1和STAT4在相互信号通路上的作用受其影响，并具有 对其他状态分子的影响。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将定义统计信息的使用作为主开关，以 调节对1型干扰素反应的积极和消极影响。目标2将机械地 定义调节状态水平的路径。目标3将拓宽1型干扰素的特征 获取其他统计数据。目标4将定义调制统计信息级别和接入的重要性 病毒感染期间1型干扰素生物学功能的改变。免疫学，病毒学， 将使用生化和分子技术，并将通过研究 接触细胞因子后的体外反应和淋巴细胞性脉络膜脑膜炎后的体内反应 野生型和转基因小鼠的病毒感染。该项目有望继续向前推进。 了解控制1型干扰素在形成对感染的免疫反应中的作用，并 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。