Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5 year-old child with severe pulmonary influenza at 2 years. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not interferon-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of interferon-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus, and respiratory syncytial virus. These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV. Overall design: Total of 72 samples, 38 samples from primary fibroblasts and 34 samples from EBV-transformed B cells, were analyzed using paired-end RNA sequence data. Out of 38 samples from primary fibroblasts, 3 control samples are paired with no stimulation vs IFNa2b stimulation. Out of 34 samples from B-cells, 3 control samples are paired with no stimuliion vs IFNa2b stimulation. In addition to healthy control subjects, patients with AR complete STAT1 (STAT1 -/-) or STAT2 (STAT2 -/-) deficiency were analyzed for comparison.

危及生命的肺部流感可由I型和III型干扰素（IFN）免疫的先天异常引发。本研究报道一例5岁儿童，其在2岁时罹患重症肺部流感。该患儿携带功能丧失型IRF9等位基因的纯合突变。其细胞在响应IFN-α2b刺激时，可激活γ激活因子（GAF，STAT1同源二聚体），但无法形成干扰素刺激基因因子3（ISGF3）三聚体（STAT1/STAT2/IRF9）。IFN-α2b诱导的患者细胞转录组范围远窄于对照细胞；不过，仍可检测到部分干扰素刺激基因转录本的诱导表达。体外实验中，患者细胞无法抑制三种呼吸道病毒的增殖：甲型流感病毒（IAV）、副流感病毒以及呼吸道合胞病毒。上述异常表型可通过转入野生型IRF9得以挽救；而在对照细胞中沉默IRF9表达则会促进病毒复制。但该患儿在体内可有效控制多种常见病毒，包括除甲型流感病毒之外的其他呼吸道病毒。本研究结果表明，依赖于人IRF9与ISGF3的I型和III型干扰素应答通路，对控制甲型流感病毒感染至关重要。实验整体设计：本研究共分析72份样本，其中38份来自原代成纤维细胞，34份来自EB病毒转化的B细胞，所有样本均采用双端RNA测序数据进行分析。在38份原代成纤维细胞样本中，3份对照样本为未刺激与IFN-α2b刺激的配对样本；在34份B细胞样本中，同样有3份对照样本为未刺激与IFN-α2b刺激的配对样本。除健康对照个体外，本研究还纳入常染色体隐性遗传完全型STAT1（STAT1 -/-）或STAT2（STAT2 -/-）缺陷患者作为对照，以进行比较分析。