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: 8112698
• 负责人: CHRISTINE A. BIRON
• 金额: $ 46.87万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112698
• 关键词: Ablation; Antiviral Agents; Autoimmune Diseases; Biochemical; Biological; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic Hepatitis C; Dependency; Disease; Exposure to; Gene Expression; Genes; Goals; Health; Immune response; Immunity; Individual; Infection; Interferon Activation; Interferon Receptor; Interferon-alpha; Interferons; Interleukin-10; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Link; Lymphocyte Subset; Lymphocytic choriomeningitis virus; Maps; Mediating; Memory; Modification; Molecular; Multiple Sclerosis; Mus; Pathway interactions; Population; Protocols documentation; Public Health; Regulation; STAT protein; STAT1 gene; STAT1 protein; STAT2 gene; STAT3 gene; STAT4 gene; STAT6 gene; Shapes; Signal Pathway; Signal Transduction; Stimulus; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Time; Transcriptional Activation; Virus; Virus Diseases; Work; base; cancer therapy; cytokine; design; in vivo; insight; public health relevance; receptor; research study; response; success

DESCRIPTION (provided by applicant): 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 effects on lymphocyte subsets. Some are paradoxical, and the mechanisms controlling type 1 IFN effects, to allow access to subset functions 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, but they can conditionally activate all of the STATs, including STAT4. 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, and subset responses linked to different pathways are being defined. Experiments are proposed in this renewal application to test the hypotheses that STATs act as molecular 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 T cell responses. Aim 1 will broaden the understanding of STAT expression and the consequences of changes for type 1 IFN access to individual STATs in different T cell subsets during infection. Aim 2 will mechanistically define the pathways regulating STAT levels. Aim 3 will test the hypothesis that STATs act as master switches by evaluating the consequences of experimentally modulating STAT levels and the mechanisms for resulting positive and negative effects on cellular responses ex vivo. Aim 4 will define the importance of modulating STAT switches for regulating biological responses during infections. 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. PUBLIC HEALTH RELEVANCE: The type 1 interferons (IFNs) mediate a wide range of biological effects, and some of these are paradoxical. This work is directed at understanding how their functions are regulated to access and control subset responses as needed in promoting health during infections. Because type 1 IFNs are also being used, with uneven success, in the treatments of cancer, chronic hepatitis C virus infections, and multiple sclerosis, and ablation protocols are being developed to block their contribution to autoimmune diseases, the results have broad relevance for the design of therapeutic protocols in protection against disease.

描述（由申请人提供）：1型干扰素（IFN），包括IFNS alpha和beta，具有有效的抗病毒作用，但也介导了广泛的免疫调节功能。这些包括对淋巴细胞亚群的影响。有些是自相矛盾的，并且控制1型IFN效应的机制允许在需要时访问子集功能的特征很差。细胞因子确实会刺激信号通路，这取决于转录的信号换能器和激活因子（STAT）1和2，但它们可以有条件地激活包括STAT4在内的所有统计数据。实验的结果表明，在感染后的早期时间大大诱导了总STAT1蛋白，而该STAT4的1型IFN激活与STAT1水平有负相关，该项目提出了该项目，该项目旨在测试1型IFN效应的假设是通过调节对不同细胞内信号通路的调节和适应性的范围和适应性的范围和适应性的，并且适用于NARTAINE和STARTIDE in VARICENTAINS。这项工作证明了假设是正确的，并且正在定义与不同途径相关的子集响应。在此续签应用中提出了实验，以测试统计数据通过增强和抑制1型IFN效应来促进细胞反应的分子转换的假设，并且STAT1和STAT4对相互信号传导途径的影响受到互惠信号通路的影响，并对其他Stat Molecules产生了影响，并且会影响其他Stat Molecules。这将通过四个针对T细胞反应的特定目标来实现。 AIM 1将扩大对STAT表达的理解以及1型IFN在感染过程中不同T细胞子集中各个统计数据的变化的后果。 AIM 2将机械地定义调节统计水平的途径。 AIM 3将通过评估实验调节统计水平的后果以及导致对细胞反应的阳性和负面影响的机制来测试统计数据作为主开关的假设。 AIM 4将定义调节统计开关对调节感染过程中生物学反应的重要性。将使用免疫，病毒学，生化和分子技术，并通过暴露于细胞因子后的体内反应进行研究，并在野生型和遗传改变小鼠的淋巴细胞性脉络性脑膜炎病毒感染后体内进行研究。该项目有望继续提高对1型IFN影响的控制在塑造感染免疫反应时的控制，并提供用于治疗应用中细胞因子的见解。但是，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的基因的价值。 公共卫生相关性：1型干扰素（IFN）介导了广泛的生物学作用，其中一些是自相矛盾的。这项工作旨在了解如何调节其功能，以根据需要在感染过程中促进健康时访问和控制子集反应。由于还使用了1型IFN，因此在癌症的治疗方法中，慢性丙型肝炎病毒感染和多发性硬化症以及消融方案正在开发以阻止其对自身免疫性疾病的贡献，因此这些结果对保护疾病的治疗方案具有广泛的相关性。