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

Hernandez, Nicholas; Melki, Isabelle; Jing, Huie; Habib, Tanwir; Huang, Susie S.Y.; Danielson, Jeffrey; Kula, Tomasz; Drutman, Scott; Belkaya, Serkan; Rattina, Vimel; Lorenzo-Diaz, Lazaro; Boulai, Anais; Rose, Yoann; Kitabayashi, Naoki; Rodero, Mathieu P.; Dumaine, Cecile; Blanche, Stéphane; Lebras, Marie-Noëlle; Leung, Man Chun; Mathew, Lisa Sara; Boisson, Bertrand; Zhang, Shen-Ying; Boisson-Dupuis, Stephanie; Giliani, Silvia; Chaussabel, Damien; Notarangelo, Luigi D.; Elledge, Stephen J.; Ciancanelli, Michael J.; Abel, Laurent; Zhang, Qian; Marr, Nico; Crow, Yanick J.; Su, Helen C.; Casanova, Jean-Laurent

y induced in IRF9-deficient cells, roughly 40% exhibit higher absolute transcript levels in the IRF9-deficient cells (data not shown). To further dissect the ISG network and dysregulation in P's B-LCL cells, we selected a subset of 84 transcripts that were strongly induced (greater than fivefold linear scale) by IFN-α2b among the healthy control subjects in our study. Of these transcripts, 37 were found to be induced (>1.5-fold) and 47 were nonresponsive in P's B-LCL cells. The transcripts were then queried for ISGs in the Interferome v2.01 database, again using a 1.5-fold cutoff to differentiate between IFN-responsive and nonresponsive genes. Of these 37 responsive and 47 nonresponsive transcripts in P's cells, 24 and 39 transcripts, respectively, were identified as ISGs in the Interferome v2.01 database. These were used for a ISG response network analysis using GeneMAN IA (Fig. 4 G) . Notable ISGs that were not induced in P's cells include genes encoding IFIT family proteins, ISG15, and components of the ISGylation system (USP18, HERC5). Consistent with the presence of ISGF3-independent transcription factors such as phosphorylated STAT1 homodimers downstream of the IFN receptor, however, mRNA of other important ISGs, such as DDX58, those for guanylate-binding proteins (GBP1, GBP4, and GBP5), ISG20, and STAT2, were induced by IFN-α2b in P's cells, albeit for most genes to lower levels when compared with control subjects. The type III IFN responsive pathway cannot easily be studied in F-SV40s and B-LCLs (Kreins et al., 2015) . Collectively, our studies indicate that P's cells express a loss-of-function IRF9 allele that severely narrows the transcriptional responses to type I IFN in multiple cell types, with functional gamma-activated factor but a lack of ISGF3 complexes resulting in the induction of a small subset of ISGs.