Systems Analysis of Cross-regulation Between Immune Receptors

免疫受体之间交叉调节的系统分析

• 批准号: 10240689
• 负责人: ALAN A ADEREM
• 金额: $ 50.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240689
• 关键词: Adaptive Immune System; Adaptor Signaling Protein; Address; Affect; Agonist; Bacteria; Bacterial Infections; Biological; Cells; Characteristics; Chromatin; Complex; Epigenetic Process; Ethylnitrosourea; Genes; Genetic Transcription; IFNAR1 gene; Immune; Immune response; Immunity; Immunologic Receptors; Individual; Induced Mutation; Inflammation; Inflammatory; Influenza; Interferon Type I; Interferons; Knock-out; Knockout Mice; Laboratories; Leucocytic infiltrate; Lung; Measures; Mediator of activation protein; Microbe; Mus; Pathogenesis; Pathology; Pathway interactions; Pattern recognition receptor; Receptor Signaling; Regulation; Regulator Genes; Repression; Role; Shapes; Signal Pathway; Signal Transduction; Specificity; Streptococcus pneumoniae; Sum; System; Systems Analysis; Systems Biology; TLR2 gene; TLR3 gene; TLR4 gene; TLR7 gene; Toll-like receptors; Validation; Virus Diseases; macrophage; microorganism; pathogen; promoter; receptor; response; superinfection; tool

Summary Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way, they must be able to tailor their activity to the specific pathogen. These cells have therefore evolved pattern recognition receptors (PRRs) that recognize conserved molecules characteristic of the microbe, which are not found within the host. Microorganisms contain multiple innate immune agonists and the macrophage response to live pathogens is shaped by the interaction of multiple signaling pathways. The aggregate response is complex and cannot be predicted from analysis of each pathway in isolation, however it is tractable using the tools of systems biology. In macrophages, this cross-regulation can arise from the simultaneous activation of multiple Toll-like receptors (TLRs). The group has demonstrated that the set of genes transcribed by simultaneous activation of the adaptor MyD88 (by TLR2, TLR4, TLR7, or TLR9) and the adaptor TICAM-1 (TRIF) (by TLR3 or TLR4) is not equivalent to the sum of the sets of genes that are activated by each adaptor alone. For example, a subset of genes whose induction is exclusive to a single adaptor is repressed by simultaneous activation of both adaptors. In their preliminary studies, the group determined that MyD88-dependent repression of TICAM-1-induced signaling is dependent on type I IFN. Multiple lines of evidence suggest that inflammatory and type I interferon pathways cross-regulate each other to shape the immune response although the precise mechanisms have yet to be fully defined. While the role of type I interferons has been extensively studied in viral infections, it has been increasingly appreciated that they also function in the response to bacteria. Understanding the cross- regulation between TLRs and type I interferon is particularly relevant to the pathogenesis of bacterial super- infection following viral infections. In this project, the Aderem laboratory will examine macrophages from mice with either targeted deletions or ENU-induced mutations in genes that our systems analysis has suggested as candidate regulators using a suite of tools that comprehensively characterize cross-regulation between TLR and IFNAR signaling in order to uncover molecules that regulate this phenomenon. They will define their mechanisms of action and impacts on their control of bacterial infections.

摘要 先天免疫细胞缺乏适应性免疫系统的精致特异性，但为了在 通过测量的方式，他们必须能够根据特定的病原体调整他们的活动。因此，这些细胞 进化的模式识别受体(PRR)识别保守的分子 微生物，在宿主内找不到。微生物含有多种天然免疫激动剂， 巨噬细胞对活体病原体的反应是由多条信号通路相互作用形成的。这个 聚合反应是复杂的，不能通过孤立地分析每一条途径来预测，然而它 使用系统生物学的工具是容易处理的。 在巨噬细胞中，这种交叉调节可能源于多个Toll样受体的同时激活 (TLRS)。该小组已经证明，通过同时激活基因转录的一组基因 适配器MyD88(通过TLR2、TLR4、TLR7或TLR9)和适配器TICAM-1(TRIF)(通过TLR3或TLR4)不是 相当于每个适配器单独激活的基因集合的总和。例如，一个子集 诱导专属于单个接头的基因通过同时激活两个接头而被抑制 适配器。 在他们的初步研究中，该小组确定MyD88依赖于TICAM-1诱导的抑制 信号转导依赖于I型干扰素。多条证据表明炎症性和I型干扰素 各种途径相互交叉调节以形成免疫反应，尽管确切的机制尚不清楚 以得到充分的定义。虽然I型干扰素在病毒感染中的作用已经被广泛研究，但它已经 越来越多的人意识到，它们也在对细菌的反应中发挥作用。理解十字架- TLRs和I型干扰素之间的调节与细菌超微结构的发病机制特别相关 病毒感染后的感染。 在这个项目中，Aderem实验室将检查具有靶向缺失或缺失的小鼠的巨噬细胞 Enu诱导的基因突变，我们的系统分析建议使用 一套工具，全面描述TLR和IFNAR信号之间的交叉调节，以便 发现调节这一现象的分子。他们将确定他们的行动机制和对 他们对细菌感染的控制。