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

III 型干扰素在呼吸道病毒感染先天免疫中的作用

• 批准号: 7996782
• 负责人: Joan E. Durbin
• 金额: $ 82.71万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996782
• 关键词: Role; Type; III; Interferon; Innate

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.

描述（由申请人提供）：III 型或-λ 干扰素（IFN）是新发现的细胞因子家族，与 I 型 IFN（α/β）一样，由病毒感染诱导。 IFN-lambda 的信号传导通过独特的受体，导致由 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效果。迄今为止，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-lambda 受体主要由上皮细胞和树突状细胞表达，因此有人认为这种细胞因子在保护粘膜免受病毒病原体感染方面可能特别重要。在甲型流感病毒感染的小鼠模型中，我们进行了新的观察，即IFN-lambda是鼻内感染诱导的主要IFN，并且发现即使在没有IFN-α/β信号传导的情况下也可以发生这种诱导。我们的假设是，这种选择性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物来检验这一假设，以研究 I 型和 III 型 IFN 在保护呼吸道方面具有重叠和独特功能的方式。我们提出以下目标：1) 证明通过 ISGF3 对 IFN 信号传导的要求，并研究 I 型和 III 型 IFN 对于有效抵御流感病毒的先天免疫保护的相对重要性。 2) 确定流感病毒感染中IFN-lambda的来源，以及响应的细胞类型。 3) 表征极化气道上皮细胞对 I 型和 III 型 IFN 的产生和反应。 4)确定流感病毒感染期间IFN-lambda在pDC成熟和功能中的作用。