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

描述（由申请人提供）： III型或λ型干扰素（IFN）组成了新发现的细胞因子家族，其与I型IFN（α/β）一样由病毒感染诱导。IFN-λ的信号传导通过独特的受体导致形成由IFN-α/β激活的相同干扰素刺激基因因子3（ISGF 3）转录复合物，因此具有非常相似的作用。到目前为止，I型和III型IFN之间的主要差异是IFN-λ受体的分布非常有限，而IFN-α/β受体是普遍表达的。由于IFN-λ受体主要由上皮细胞和树突状细胞表达，因此已经表明这种细胞因子在保护免受病毒病原体的粘膜感染中可能特别重要。在A型流感病毒感染的小鼠模型中，我们已经进行了新的观察，即IFN-λ是鼻内感染诱导的主要IFN，并且已经发现这种诱导甚至可以在没有IFN-α/β信号传导的情况下发生。我们的假设是，这种交替调节的抗病毒IFN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物来验证这一假设，以研究I型和III型IFN在呼吸道保护中具有重叠功能与独特功能的方式。我们提出以下目标：1）证明通过ISGF 3进行IFN信号传导的需要，并研究I型和III型IFN对于针对流感病毒的有效先天免疫保护的相对重要性。2)确定流感病毒感染中IFN-λ的来源以及相应的细胞类型。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)确定流感病毒感染期间IFN-λ在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.