The Role of Type III Interferon in Innate Immunity to Respiratory Virus Infection

描述（由申请人提供）：III型干扰素（IFN）是一种新发现的细胞因子家族，与I型干扰素（α / β）一样，由病毒感染诱导。IFN-lambda的信号通过一种独特的受体，导致IFN- α / β激活的相同干扰素刺激基因因子3 （ISGF3）转录复合物的形成，因此具有非常相似的作用。到目前为止，I型和III型ifn之间的主要区别是IFN-lambda受体的分布非常有限，而ifn - α / β受体则普遍表达。由于ifn受体主要由上皮细胞和树突状细胞表达，因此有人认为该细胞因子可能在保护粘膜免受病毒病原体感染方面具有特别重要的作用。在甲型流感病毒感染的小鼠模型中，我们进行了新的观察，发现IFN-lambda是鼻内感染诱导的主要IFN，并且发现这种诱导即使在缺乏IFN- α / β信号传导的情况下也会发生。我们的假设是，这种可调节的抗病毒干扰素家族在保护宿主免受呼吸道病毒感染方面具有独特的作用。我们将使用基因靶向小鼠和原代气道上皮细胞培养来验证这一假设，以研究I型和III型ifn在呼吸道保护中重叠与独特功能的方式。我们提出以下目标：1)通过ISGF3证明IFN信号的必要性，并研究I型和III型IFN在有效的抗流感病毒先天免疫保护中的相对重要性。2)确定流感病毒感染中IFN-lambda的来源以及应答的细胞类型。3)表征极化气道上皮细胞对I型和III型ifn的产生和反应性。4)确定IFN-lambda在流感病毒感染时pDC成熟和功能中的作用。

DESCRIPTION (provided by applicant): Type III, or-lambda, interferons (IFN) make up a newly discovered family of cytokines which, like the type I IFNs (alpha/beta), are induced by virus infection. IFN-lambda's signaling, through a unique receptor, leads to formation of the same interferon stimulated gene factor 3 (ISGF3) transcription complex activated by IFN- alpah/beta, and therefore has very similar effects. The primary difference noted so far between the type I and type III IFNs is the very limited distribution of the IFN-lambda receptor, in contrast to the IFN-alpha/beta receptor which is ubiquitously expressed. As the IFN-lambda receptor is expressed primarily by epithelial cells and dendritic cells, it has been suggested that this cytokine may be of particular importance in protection from mucosal infections by viral pathogens. In a mouse model of influenza A virus infection we have made the novel observation that IFN-lambda is the primary IFN induced by intranasal infection, and have found that this induction can occur even in the absence of IFN-alpha/beta signaling. It is our hypothesis that this alternatively regulated family of anti-viral IFNs has a unique role in protecting the host from respiratory virus infection. We will test this hypothesis using gene-targeted mice and primary airway epithelial cell cultures to investigate the ways in which type I and type III IFNs have overlapping versus distinctive functions in protection of respiratory tract. We propose the following aims: 1) Demonstrate the requirement for IFN signaling via ISGF3, and investigate the relative importance of type I and type III IFNs for effective innate immune protection against influenza virus. 2) Identify the source(s) of IFN-lambda in influenza virus infection, as well the responding cell types. 3) Characterize production of, and responsiveness to, type I and type III IFNs by polarized airway epithelial cells. 4) Determine the role of IFN-lambda in pDC maturation and function during influenza virus infection.