Systems Analysis of Cross-regulation Between Immune Receptors

总结 先天性免疫细胞缺乏适应性免疫系统的精确特异性，但为了以一种特异性免疫应答， 为了测量，它们必须能够针对特定的病原体调整它们的活性。因此，这些细胞 进化的模式识别受体（PRR），其识别具有免疫原性的保守分子。 微生物，在宿主体内找不到。微生物含有多种先天免疫激动剂， 巨噬细胞对活病原体的反应是由多种信号传导途径的相互作用形成的。的 聚集反应是复杂的，不能通过单独分析每个途径来预测，但是， 是可以用系统生物学的工具来处理的。 在巨噬细胞中，这种交叉调节可以由多个Toll样受体的同时激活引起 （TLR）。该小组已经证明，通过同时激活转录的基因组， 衔接子MyD 88（通过TLR 2、TLR 4、TLR 7或TLR 9）和衔接子TICAM-1（TRIF）（通过TLR 3或TLR 4）不被 相当于由每个衔接子单独激活的基因组的总和。例如， 只有一个衔接子才能诱导的基因被两个衔接子同时激活所抑制 适配器。 在他们的初步研究中，该小组确定了MyD 88依赖性的TICAM-1诱导的抑制作用。 信号传导依赖于I型IFN。多种证据表明，炎症和I型干扰素 通路相互交叉调节以形成免疫反应，尽管精确的机制还没有 被完全定义。虽然I型干扰素在病毒感染中的作用已被广泛研究，但它在病毒感染中的作用仍有待进一步研究。 越来越多的人认识到，它们也在对细菌的反应中发挥作用。理解十字架- TLR和I型干扰素之间的调节与细菌性超级细菌的发病机制特别相关， 病毒感染后的感染。 在这个项目中，Aderem实验室将检查来自小鼠的巨噬细胞， ENU诱导的基因突变，我们的系统分析表明，作为候选监管机构使用 一套工具，全面表征TLR和IFNAR信号传导之间的交叉调节， 发现调节这种现象的分子。它们将确定其作用机制和对以下方面的影响： 控制细菌感染。

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.