Reuter Antje, Soubies Sebastien, Härtle Sonja, Schusser Benjamin, Kaspers Bernd, Staeheli Peter, Rubbenstroth Dennis
Institute for Virology, University of Freiburg, Freiburg, Germany.
J Virol. 2014 Mar;88(5):2835-43. doi: 10.1128/JVI.02764-13. Epub 2013 Dec 26.
Interferons (IFNs) are essential components of the antiviral defense system of vertebrates. In mammals, functional receptors for type III IFN (lambda interferon [IFN-λ]) are found mainly on epithelial cells, and IFN-λ was demonstrated to play a crucial role in limiting viral infections of mucosal surfaces. To determine whether IFN-λ plays a similar role in birds, we produced recombinant chicken IFN-λ (chIFN-λ) and we used the replication-competent retroviral RCAS vector system to generate mosaic-transgenic chicken embryos that constitutively express chIFN-λ. We could demonstrate that chIFN-λ markedly inhibited replication of various virus strains, including highly pathogenic influenza A viruses, in ovo and in vivo, as well as in epithelium-rich tissue and cell culture systems. In contrast, chicken fibroblasts responded poorly to chIFN-λ. When applied in vivo to 3-week-old chickens, recombinant chIFN-λ strongly induced the IFN-responsive Mx gene in epithelium-rich organs, such as lungs, tracheas, and intestinal tracts. Correspondingly, these organs were found to express high transcript levels of the putative chIFN-λ receptor alpha chain (chIL28RA) gene. Transfection of chicken fibroblasts with a chIL28RA expression construct rendered these cells responsive to chIFN-λ treatment, indicating that receptor expression determines cell type specificity of IFN-λ action in chickens. Surprisingly, mosaic-transgenic chickens perished soon after hatching, demonstrating a detrimental effect of constitutive chIFN-λ expression. Our data highlight fundamental similarities between the IFN-λ systems of mammals and birds and suggest that type III IFN might play a role in defending mucosal surfaces against viral intruders in most if not all vertebrates.
干扰素（IFNs）是脊椎动物抗病毒防御系统的重要组成部分。在哺乳动物中，III型干扰素（λ干扰素[IFN-λ]）的功能性受体主要存在于上皮细胞上，并且已证明IFN-λ在限制粘膜表面的病毒感染中起关键作用。为了确定IFN-λ在鸟类中是否发挥类似作用，我们制备了重组鸡IFN-λ（chIFN-λ），并使用具有复制能力的逆转录病毒RCAS载体系统生成组成性表达chIFN-λ的嵌合转基因鸡胚胎。我们能够证明，chIFN-λ在体内外以及富含上皮组织和细胞培养系统中均能显著抑制包括高致病性甲型流感病毒在内的多种病毒株的复制。相比之下，鸡成纤维细胞对chIFN-λ的反应较差。当在体内应用于3周龄的鸡时，重组chIFN-λ强烈诱导富含上皮的器官（如肺、气管和肠道）中IFN反应性Mx基因的表达。相应地，发现这些器官表达假定的chIFN-λ受体α链（chIL28RA）基因的高转录水平。用chIL28RA表达构建体转染鸡成纤维细胞使这些细胞对chIFN-λ处理有反应，表明受体表达决定了鸡中IFN-λ作用的细胞类型特异性。令人惊讶的是，嵌合转基因鸡在孵化后不久就死亡了，这表明组成性chIFN-λ表达具有有害作用。我们的数据突出了哺乳动物和鸟类IFN-λ系统之间的基本相似性，并表明III型干扰素可能在大多数（如果不是全部）脊椎动物中在保护粘膜表面免受病毒入侵方面发挥作用。
