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

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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.****************