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: 8528309
• 负责人: CHRISTINE A. BIRON
• 金额: $ 44.17万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528309
• 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IFN α和IFN β，具有有效的抗病毒作用，但也介导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，和机制控制1型干扰素的影响，允许访问子集功能时，需要的，是很差的特点。细胞因子确实刺激信号传导途径，这取决于信号转导和转录激活因子（STAT）1和2，但它们可以有条件地激活所有STAT，包括STAT 4。由于实验证明总STAT1蛋白在感染后的早期被显著诱导，并且STAT4的1型IFN活化与STAT1水平负相关，因此本项目提出测试1型IFN效应由进入不同细胞内信号传导途径的调节控制的假设，并且这种调节在对病毒感染的先天性和适应性免疫应答期间是必需的和递送的。这项工作已经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。在该更新申请中提出实验以测试以下假设：STAT通过增强和抑制1型IFN效应在促进细胞应答中充当分子开关，并且STAT 1和STAT 4对相互信号传导途径的效应受其他STAT分子的影响并对其产生影响。这将通过关注T细胞反应的四个具体目标来实现。目的1将拓宽STAT表达的理解和1型IFN在感染过程中进入不同T细胞亚群中的单个STAT的变化的后果。目的2将从机制上定义调节STAT水平的途径。目的3将通过评估实验性调节STAT水平的后果以及对离体细胞应答产生积极和消极影响的机制来检验STAT充当主开关的假设。目的4将定义在感染期间调节STAT开关以调节生物反应的重要性。将使用免疫学、病毒学、生物化学和分子技术，并通过研究暴露于细胞因子后的离体反应和野生型和基因改变小鼠中淋巴细胞性脉络丛脑膜炎病毒感染后的体内反应来推进这项工作。该项目有望继续推进对1型IFN影响的控制的理解，以形成对感染的免疫反应，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。 公共卫生相关性：1型干扰素（IFN）介导广泛的生物学效应，其中一些是自相矛盾的。这项工作旨在了解它们的功能是如何调节的，以根据感染期间促进健康的需要访问和控制子集反应。由于1型干扰素也被用于治疗癌症，慢性丙型肝炎病毒感染和多发性硬化症，并且正在开发消融方案以阻止其对自身免疫性疾病的贡献，因此这些结果对于设计预防疾病的治疗方案具有广泛的相关性。

项目成果

TRIM68 negatively regulates IFN-β production by degrading TRK fused gene, a novel driver of IFN-β downstream of anti-viral detection systems.

• DOI: 10.1371/journal.pone.0101503
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wynne C;Lazzari E;Smith S;McCarthy EM;Ní Gabhann J;Kallal LE;Higgs R;Greco A;Cryan SA;Biron CA;Jefferies CA
• 通讯作者: Jefferies CA

CD8 T cells in innate immune responses: using STAT4-dependent but antigen-independent pathways to gamma interferon during viral infection.

• DOI: 10.1128/mbio.01978-14
• 发表时间: 2014-10-21
• 期刊: mBio
• 影响因子: 6.4
• 作者: Suarez-Ramirez JE;Tarrio ML;Kim K;Demers DA;Biron CA
• 通讯作者: Biron CA

The role of STAT1 in viral sensitization to LPS.

STAT1 在病毒对 LPS 致敏中的作用。

• DOI: 10.1179/096805103225002575
• 发表时间: 2003
• 期刊: Journal of endotoxin research
• 作者: Durbin,Joan;Doughty,Leslie;Nguyen,Ken;Caligiuri,Michael;VanDeusen,Jeff;Biron,Christine
• 通讯作者: Biron,Christine