Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1
Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1
复制标题
DOI：
10.1128/jvi.00283-13
复制
发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Staeheli, Peter
中科院分区：
文献类型：
--
作者：
Kallfass, Carsten;Lienenklaus, Stefan;Staeheli, Peter
先天宿主对流感病毒的防御很大程度上依赖于I型干扰素（IFN）系统。然而，令人惊讶的是，对感染肺中IFN的细胞来源知之甚少。为了澄清这个问题，我们使用了一只含有萤火虫荧光素酶基因的报告小鼠来代替ifn - β编码区。通过肺荧光素酶和细胞标记物的同时免疫染色或通过产生在特定细胞类型中只表达荧光素酶的条件报告小鼠来鉴定产生ifn - β的细胞。研究人员使用了两种不同的甲型流感病毒株，它们要么编码非结构蛋白1 (NS1)，要么不编码非结构蛋白1 (NS1)， NS1强烈抑制感染细胞的先天免疫反应。我们发现上皮细胞和肺巨噬细胞（代表流感病毒的主要宿主细胞）表现出强烈的ifn - β反应，然而，如果感染病毒能够产生NS1，这种反应就会严重减少和延迟。有趣的是，在感染野生型甲型流感病毒48小时后，表达或缺乏巨噬细胞标记的CD11c（+）细胞群产生了大量的ifn - β。我们的研究结果表明，病毒编码的ifn拮抗因子NS1特异性地解除了上皮细胞和肺巨噬细胞的武装，否则它们将成为抵抗流感病毒感染的早期反应的主要介质。
The innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-beta-coding region. IFN-beta-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-beta responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c(+) cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-beta at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.