Cellular sources of interferon-beta in virus-infected organs of the mouse

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The antiviral host defense is largely dependent on the type I interferon (IFN-alpha/beta) system. However, surprisingly little is known about the cellular sources of type I IFN in infected tissues. To investigate this issue, we are employing a transgenic reporter mouse that contains the firefly luciferase gene in place of the IFN-beta coding region. In this reporter mouse, IFN-beta-producing cells can be identified by simultaneous immunostaining of virus-infected organs for luciferase and cellular markers, or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Using this system we recently demonstrated that astrocytes are surprisingly potent producers of IFN-beta in the brain of La Crosse virus-infected mice. We further showed that influenza virus-infected macrophages and lung epithelial cells readily synthesize IFN-beta if the virus-encoded IFN-antagonistic factor NS1 is not disarming these cells. By a classical breeding strategy we recently generated reporter mice that lack functional type I IFN receptors. These mice represent a novel tool to investigate the question which cell types require a positive feedback loop (priming) for efficient type I IFN synthesis in response to viral infection. The current project has two main goals: (i) to evaluate the hypothesis derived from our previous work that astrocytes are the main source of IFN-beta in virus-infected brains, irrespective of which neurotropic viruses is at work, and (ii) to identify priming-dependent and priming-independent cell types which produce large amounts of type I IFN after systemic or local viral infection. To address the first question, we will try to identify the cellular sources of IFN-beta in brains of mice infected with either Theilers murine encephalitis virus or rabies virus. To address the second question, we will try to reveal the identity of IFN-beta-producing cells in mice infected either with Thogoto virus or a Rift Valley fever virus variant which strongly activates expression of type I IFN genes both in mice lacking or possessing functional type I IFN receptors.