Defective RNA sensing by RIG-I in severe influenza virus infection
Defective RNA sensing by RIG-I in severe influenza virus infection
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DOI：
10.1111/cei.13120
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发表时间：
2018-06-01
影响因子：
4.6
通讯作者：
Mogensen, T. H.
中科院分区：
文献类型：
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作者：
Jorgensen, S. E.;Christiansen, M.;Mogensen, T. H.
流感病毒感染引起世界范围的季节性流行病。虽然流感通常是一种轻微的疾病，但少数患者会经历非常严重的暴发性疾病过程。先前的研究已经证明了I型干扰素（IFN）在流感期间的抗病毒应答中的作用。然而，到目前为止，干扰素调节因子（IRF）7缺乏症是人类中描述的严重流感的唯一遗传原因。在这项研究中，我们提出了一个严重的甲型流感病毒（IAV）H1N1感染的患者在2009年猪流感大流行。通过全外显子组测序，我们鉴定了两种变体，p.R71H和p.P885S，分别位于编码RNA传感器视黄酸诱导基因1（RIG-I）的DExD/H-box解旋酶58（DDX 58）的半胱天冬酶激活和募集结构域（CARD）和RNA结合结构域。这些变体显著损害RIG-I的信号传导活性。类似地，患者细胞表现出对RIG-I配体的抗病毒应答降低以及对IAV的促炎应答增加，这表明先天免疫应答的失调与免疫病理学的增加。我们认为，这些RIG-I变异可能导致严重的流感在这个病人，并主张RIG-I变异应寻求在未来的研究中的遗传因素影响单链RNA病毒感染。
Influenza virus infection causes worldwide seasonal epidemics. Although influenza is usually a mild disease, a minority of patients experience very severe fulminating disease courses. Previous studies have demonstrated a role for type I interferon (IFN) in anti-viral responses during influenza. So far, however, IFN regulatory factor (IRF)7 deficiency is the only genetic cause of severe influenza described in humans. In this study we present a patient with severe influenza A virus (IAV) H1N1 infection during the 2009 swine flu pandemic. By whole exome sequencing we identified two variants, p.R71H and p.P885S, located in the caspase activation and recruitment domain (CARD) and RNA binding domains, respectively, of DExD/H-box helicase 58 (DDX58) encoding the RNA sensor retinoic acid inducible gene 1 (RIG-I). These variants significantly impair the signalling activity of RIG-I. Similarly, patient cells demonstrate decreased antiviral responses to RIG-I ligands as well as increased proinflammatory responses to IAV, suggesting dysregulation of the innate immune response with increased immunopathology. We suggest that these RIG-I variants may have contributed to severe influenza in this patient and advocate that RIG-I variants should be sought in future studies of genetic factors influencing single-stranded RNA virus infections.