Influenza infection is common worldwide with many individuals affected each year during epidemics and occasionally pandemics. Previous studies in animal models and a few human cases have established an important role of innate type I and III interferon (IFN) for viral elimination and mounting of antiviral responses. However, genetic and immunological determinants of very severe disseminated influenza virus infection in humans remain incompletely understood. Here, we describe an adult patient with severe influenza virus A (IAV) infection, in whom we identified a rare variant E331V in IFN regulatory factor (IRF)7 by whole-exome sequencing. Examination of patient cells demonstrated a cellular phenotype suggesting functional IRF7 impairment, since priming with IFN was almost abolished and IFN responses to IAV were significantly impaired in patient cells. Moreover, IAV replication was significantly higher in patient cells than in controls. Finally, expression of IRF7 E331V in HEK293 cells demonstrated significantly reduced activation of both IFNA7 and IFNB promoters in a luciferase reporter gene expression assay compared to IRF7 wild type. These findings provide further support for the essential role of IRF7 in amplifying antiviral IFN responses to ensure potent and sustained IFN responses during influenza virus infection in humans.

中文翻译：

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IRF7变异和严重流感患者的干扰素引发缺陷和抗病毒反应受损。

流感感染在世界范围内很普遍，每年在流行病和偶尔的大流行期间都会有许多人受到感染。先前在动物模型和一些人类病例中进行的研究已经确定了先天I型和III型干扰素（IFN）在消除病毒和增强抗病毒反应方面的重要作用。然而，关于人类中非常严重的传播性流感病毒感染的遗传和免疫学决定因素仍未完全了解。在这里，我们描述了一名患有严重甲型流感病毒（IAV）感染的成年患者，其中我们通过全外显子组测序在IFN调节因子（IRF）7中鉴定了一种罕见的E331V变异体。对患者细胞的检查显示细胞表型提示功能性IRF7损伤，因为几乎没有使用IFN引发，并且在患者细胞中IFN对IAV的反应明显受损。此外，患者细胞中的IAV复制明显高于对照组。最后，表达IRF7 E331V在HEK293细胞中证实显著降低两者的活化IFNA7和IFNB相比启动子萤光素酶报道基因表达测定IRF7野生型。这些发现为IRF7在扩大抗病毒IFN反应以确保在人类流感病毒感染期间确保有效和持续的IFN反应中的重要作用提供了进一步的支持。