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

小鼠病毒感染器官中干扰素-β的细胞来源

基本信息

批准号：
245020675
负责人：
Professor Dr. Peter Stäheli
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie und Hygiene (IMMH)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/245020675?language=en
关键词：
Cellular sources interferon beta virus

项目摘要

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.

抗病毒宿主防御在很大程度上依赖于I型干扰素（IFN-α/β）系统。然而，令人惊讶的是，很少有人知道的细胞来源的I型干扰素在感染的组织。为了研究这个问题，我们采用了一种转基因报告小鼠，含有萤火虫荧光素酶基因的地方IFN-β编码区。在这种报告小鼠中，可以通过同时对病毒感染的器官进行荧光素酶和细胞标志物的免疫染色，或通过产生仅在限定的细胞类型中表达荧光素酶的条件报告小鼠来鉴定IFN-β产生细胞。利用这个系统，我们最近证明，星形胶质细胞是令人惊讶的强有力的生产者IFN-β在拉克罗斯病毒感染的小鼠的大脑。我们进一步表明，如果病毒编码的IFN拮抗因子NS1不解除这些细胞的武装，流感病毒感染的巨噬细胞和肺上皮细胞很容易合成IFN-β。通过经典的育种策略，我们最近产生的报告小鼠，缺乏功能性I型IFN受体。这些小鼠代表了一种新的工具，以调查的问题，细胞类型需要一个积极的反馈回路（引发），有效的I型IFN合成响应病毒感染。目前的项目有两个主要目标：（i）评估来自我们以前的工作，星形胶质细胞是病毒感染的大脑中IFN-β的主要来源的假设，无论是哪种嗜神经病毒在工作，和（ii）确定引发依赖性和引发非依赖性细胞类型，产生大量的I型IFN后，全身或局部病毒感染。为了解决第一个问题，我们将尝试识别感染Theilers鼠脑炎病毒或狂犬病病毒的小鼠脑中IFN-β的细胞来源。为了解决第二个问题，我们将试图揭示身份的IFN-β产生细胞感染的小鼠Thogoto病毒或裂谷热病毒的变种，强烈激活表达的I型IFN基因在小鼠缺乏或拥有功能性I型IFN受体。