Temporal-quantitative control of IRF-3 and NF-kB upon pathogen recognition in single cells and living tissue

点击翻译按钮获取中文摘要

The induction of type-I interferon (IFN) genes in response to viral infection is an essential process of innate immunity. Following recognition of viral RNA a complex signal transduction pathway eventually activates IRFs (interferon regulatory factors) 3 and 7 and NF-kB (nuclear factor kB). These factors mediate the transcriptional induction of type-I interferon (IFN) and other antiviral genes. Strikingly, individual cells exhibit a yet unpredictable variation in the expression of IFN and its timing. Our recent work provides for the first time a comprehensive analysis of IFN induction and action signalling at single-cell resolution (Rand et al., Molecular Systems Biology, in revision). However, the mechanistic basis of IFN expression dynamics remains unclear. With the proposed research project I want to elucidate how the recognition of pathogen patterns is translated into spatio-temporal signalling dynamics at single-cell level. It is known that a disproportionate production of type-I IFN can play an important role in the inability to control viral infections and in autoimmune disorders. Elucidating the temporal-spatial dynamics of the IRF-3 / NF-kB-mediated induction depending on variable conditions such as pathogenic load, cytokine environment or tissue structure will help to understand how appropriate control on IFN production is maintained. Therefore, I will perform time-resolved quantitative studies to investigate the concerted regulation of IRF-3 and NF-kB following recognition of dsRNA by the cell. With this I will elucidate the impact of various conditions of an inflammatory environment and the relevance of single-cell dynamics in living tissue. Data from these quantitative studies will be used to create a mathematical model with the aim to be able to predict IFN expression dynamics. The overall use of this work will be to allow predictive assumptions on the course of the early immune response following infection or vaccination. Furthermore, the results of this work can serve as a roadmap for related signalling pathways.