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

描述(申请人提供)：III型或-lambda干扰素(干扰素)组成了一个新发现的细胞因子家族，与I型IFN(α/β)一样，是由病毒感染诱导的。干扰素-lambda的信号通过一种独特的受体，导致由干扰素-α/β激活的相同的干扰素刺激基因因子3(ISGF3)转录复合体的形成，因此具有非常相似的作用。到目前为止，I型和III型IFN之间的主要区别是干扰素-lambda受体的分布非常有限，而干扰素-α/β受体是普遍表达的。由于干扰素-lambda受体主要由上皮细胞和树突状细胞表达，因此该细胞因子在保护黏膜免受病毒病原体感染方面可能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，发现干扰素-lambda是鼻腔感染诱导的主要干扰素，并发现即使在没有干扰素-α/β信号的情况下，这种诱导也可以发生。我们的假设是，这个受交替调控的抗病毒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呼吸道上皮细胞培养来验证这一假设，以调查I型和III型IFN在保护呼吸道方面重叠和不同功能的方式。我们提出了以下目标：1)论证了通过ISGF3传递干扰素信号的必要性，并研究了I型和III型IFN对流感病毒的有效天然免疫保护的相对重要性。2)确定流感病毒感染中干扰素的来源(S)，以及相应的细胞类型。3)表征极化的呼吸道上皮细胞产生I型和III型IFN及其反应性。4)确定在流感病毒感染过程中干扰素-lambda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.