Purinergic alarmin signaling in acute and chronic viral Infections

急性和慢性病毒感染中的嘌呤能警报蛋白信号传导

• 批准号: 459963363
• 负责人: Professor Dr. Max Löhning
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie (einschließlich Arbeitsbereich Physikalische Medizin)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/459963363?language=en
• 关键词: Purinergic; alarmin; signaling; acute; chronic

The cellular immune reaction against viral pathogens is a tightly regulated process orchestrated by intra- and extracellular cues to maintain a balance between antiviral immunity and tissue-destructive immunopathology. Owing to complex cell-cell interactions and spatiotemporally restricted processes, the mechanisms driving adaptive and innate immune responses remain incompletely understood. Yet, the identification of novel regulators is critical for the design of targeted therapeutics.In recent years, we and others have shown that alarmins, in particular the cytokine interleukin-33 (IL-33), play a central role in both induction and regulation of acute and chronic inflammation. Released upon necrotic cell death, IL-33 can equally promote effector T cell activity or suppressive and tissue-regenerative properties of regulatory T cells. Besides the well-studied alarmins IL-33, IL-1alpha or S100 proteins, metabolites such as the purine adenosine-triphosphate (ATP) have emerged as critical indicators of tissue damage at sites of inflammation and key regulators of T cell responses. ATP can bind to purinergic receptors on T cells and thereby induce a dose-dependent cellular Ca2+ ion influx. This in turn fine-tunes a multitude of intracellular signaling pathways and can drastically affect T cell metabolism and activity.We have studied the expression patterns of various purinergic receptors of the P2X family and identified novel candidates that are selectively expressed by activated antiviral T cells and induced by inflammatory signals. Hence, we here propose to study the role of ATP-P2X signaling in immune homeostasis and during acute and chronic viral infection with lymphocytic choriomeningitis virus (LCMV). Using newly generated knock-out and knock-in mouse lines, we will study the T cell-intrinsic requirement of ATP-P2X signaling for functional T cell expansion, differentiation, acquisition of effector functions and T cell exhaustion. Further, these experiments will be complemented by state-of-the-art next generation sequencing approaches and metabolic assays to assess the molecular consequences of defective ATP sensing. Lastly, we will investigate the therapeutic potential of established pharmacologic inhibitors of ATP-P2X signaling in preventing virus-induced immunopathology with the aim to pave the way for pre-clinical studies.

针对病毒病原体的细胞免疫反应是由细胞内和细胞外线索协调的严格调节的过程，以维持抗病毒免疫和组织破坏性免疫病理学之间的平衡。由于复杂的细胞-细胞相互作用和时空限制的过程，驱动适应性和先天性免疫应答的机制仍然不完全清楚。近年来，我们和其他人已经表明，alarmins，特别是细胞因子白细胞介素-33（IL-33），在急性和慢性炎症的诱导和调节中发挥着核心作用。在坏死性细胞死亡后释放，IL-33可以同等地促进效应T细胞活性或调节性T细胞的抑制和组织再生特性。除了研究充分的alarmins IL-33，IL-1 α或S100蛋白外，代谢产物如嘌呤腺苷三磷酸（ATP）已成为炎症部位组织损伤的关键指标和T细胞反应的关键调节因子。ATP可与T细胞上的嘌呤能受体结合，从而诱导剂量依赖性的细胞内Ca 2+离子内流。这反过来又微调了众多的细胞内信号传导途径，可以大大影响T细胞的代谢和activity.We的各种嘌呤受体的P2 X家族的表达模式进行了研究，并确定了新的候选人，选择性表达的激活抗病毒T细胞和炎症信号诱导。因此，我们在这里提出研究的作用，ATP-P2 X信号在免疫稳态和急性和慢性病毒感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）。使用新产生的敲除和敲入小鼠系，我们将研究ATP-P2 X信号传导对功能性T细胞扩增、分化、获得效应子功能和T细胞耗竭的T细胞内在需求。此外，这些实验将通过最先进的下一代测序方法和代谢测定来补充，以评估缺陷ATP传感的分子后果。最后，我们将研究已建立的ATP-P2 X信号传导药理学抑制剂在预防病毒诱导的免疫病理学方面的治疗潜力，旨在为临床前研究铺平道路。