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

Mice either homozygous for an Irf7-null allele or heterozygous for a Gata2-null allele have also been characterized. Although Gata2 +/− mice were found to possess significantly reduced pDC counts, they have not been studied for infectious diseases, as research has instead focused on hematopoietic and vascular integrity (Johnson et al., 2012; Collin et al., 2015; Onodera et al., 2016) . Similarly, the integrity and function of the type III IFN signaling pathway remains largely unexplored in Gata2 +/− mice. Irf7 −/− mice display reduced induction of IFN-α/β following either viral infection or stimulation with synthetic TLR agonists, as well as increased vulnerability to infection with HSV-1 and encephalomyocarditis virus (Sato et al., 1998; Honda et al., 2005) . More recently, Irf7 was identified as one of 25 differentially expressed genes between C57BL/6J and DBA/2J mice infected with influenza A virus (IAV) that overlapped with differentially expressed genes identified in other siRNA screens to be important for IAV replication (Wilk et al., 2015) . Furthermore, Irf7 −/− mice that were derived on a C57BL/6 background that does not contain a functional Mx1 allele, when infected by influenza virus, experienced greater morbidity and mortality than control mice (Wilk et al., 2015) . Most other studies analyzing the genetics and immunology of influenza infection have also been performed in Mx1-deficient mice and thus should be reexamined in mice expressing Mx1, due to the crucial role of this IFN-stimulated gene (ISG) product in mouse immunity to influenza virus (Staeheli et al., 1988; Iwasaki and Pillai, 2014; Ciancanelli et al., 2016) . Significantly, however, Ifnb1 −/− mice are substantially more sensitive to IAV, even in an Mx1-positive background (Koerner et al., 2007) . Similar studies in an Mx1-positive background have demonstrated crucial roles for IFN AR1, TLR7, and MyD88 signaling in defense against influenza infection (Koerner et al., 2007; Kaminski et al., 2012) . Mice with impaired type III IFN immunity have been shown to display marginally elevated influenza virus replication relative to WT mice, and to be hypersensitive to influenza virus when type I IFN signaling was also ablated (Mordstein et al., 2008) . Overall, type I and/or type III IFN immunity seem to be crucial for protective immunity against influenza virus in both humans and mice. Not all inborn errors of human type I and III IFN immunity, however, underlie severe influenza, at least among the few human patients reported. We therefore hypothesized that defects of type I and III IFNs other than GATA2 and IRF7 deficiency may underlie severe influenza in other individuals. Thus, we set out to analyze the whole-exome sequencing (WES) data of 20 children with severe influenza by first focusing on type I and III IFN-related genes.