Purinergic alarmin signaling in acute and chronic viral Infections

点击翻译按钮获取中文摘要

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.