Type I interferon receptor signalling as a master switch for the negative regulation of cytokine networks.

病毒感染是通过诱导先天免疫反应来控制的。作为第一道防线，细胞在感知到病毒的存在后会产生一组被称为I型干扰素（ifn）的细胞因子。这些I型IFN包括IFN- α和IFN- β，由表达IFN a/ß受体（IFNAR）的细胞检测。通过IFNAR发出的信号引起细胞内的多种变化，从而促进病毒的清除。在某些情况下，这种反应会导致细胞因子的过量产生，导致所谓的细胞因子风暴，这可能是非常有毒的。例如，这是严重急性呼吸系统综合症（SARS）和某些流感病毒感染病例死亡的一个原因。这种现象并不局限于病毒。细菌是女性中毒性休克综合征的罪魁祸首。细胞因子风暴背后的相同机制也可能有助于减少毒性反应，但会引起不必要的副作用，例如在过度强烈的炎症期间。我们有证据表明IFNAR信号通路可能在关闭细胞中多种细胞因子的产生中发挥关键和意想不到的作用。在缺乏IFNAR的转基因小鼠中，感染很快就会致命。通过骨髓移植，我们制造了嵌合小鼠，其白细胞缺乏IFNAR，但体内所有其他细胞都表达IFNAR。在暴露于通常被认为是非常安全的病毒之后，这些老鼠很快就屈服于细胞因子风暴。这表明不能检测到I型IFN产生的白细胞不能控制其他细胞因子的产生。这项研究计划将培训多达8名高素质的科学家。这样，我们将阐明通过IFNAR信号传导在调节细胞因子网络中的作用。我们期望发现控制细胞因子的新机制。利用这些知识，我们也期望能够开发出抑制过度炎症和细胞因子风暴的策略。

Viral infections are controlled by the induction of an innate immune response. As a first line of defense, a set of cytokines known as type I interferons (IFNs) are produced by cells after they sense the presence of viruses. These type I IFNs include IFN-alpha and IFN-beta and are detected by cells expressing the IFN a/ß receptor (IFNAR). Signalling through the IFNAR causes multiple changes inside cells that facilitate the clearance of viruses. In some cases, this response results in excessive production of cytokines, leading to a so-called cytokine storm that can be very toxic. This is a cause of mortality in cases of severe acute respiratory syndrome (SARS) and infection with some strains of influenza, for example. This phenomenon is not limited to viruses. Bacteria are responsible for toxic shock syndrome in women. The same mechanisms underlying cytokine storms may also contribute to less toxic responses that nevertheless cause unwanted side effects, such as during overly robust inflammation.We have evidence that the IFNAR signalling pathway might play a critical and unexpected role in shutting down the production of a wide variety of cytokines in cells. Infections quickly become fatal in transgenic mice lacking the IFNAR. Using bone marrow transplantation, we made chimeric mice whose white blood cells lacked the IFNAR but all other cells in the body expressed it. After exposure to what is normally considered a very safe virus, these mice quickly succumbed to a cytokine storm. This suggests that white blood cells that cannot detect the type I IFN being produced are unable to control the production of other cytokines. Up to eight highly-qualified scientists will be trained in this research program. In so doing, we will elucidate the role of signalling through the IFNAR in regulating cytokine networks. We expect to discover new mechanisms controlling cytokines. Using this knowledge, we also anticipate being able to develop strategies to suppress excessive inflammation and cytokine storms.