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

Three patients had severe influenza at ages 18, 31, and 54 yr, associated with the abnormal development of multiple myeloid and lymphoid subsets, including pDCs (Sologuren et al., 2018) . Influenza was the first severe infection in only one of these patients (Pasquet et al., 2013; Sole-Violan et al., 2013) . The mechanism underlying severe influenza in GATA2-deficient patients is unknown, but might involve their lack of pDCs, which are among the most potent type I and type III IFN-producing cells due to their high basal expression of IRF7 (Coccia et al., 2004; Asselin-Paturel et al., 2005; Osterlund et al., 2007; Lauterbach et al., 2010; Ning et al., 2011) . Intriguingly, inborn errors of TLR3or MDA5-dependent production of IFNs have not been shown to underlie severe influenza (Zhang et al., 2007; Lamborn et al., 2017) . Interestingly, STAT1-, STAT2-, JAK1-, TYK2-, IFN AR2-, and IL10RB-mutated patients, with defective type I and/or III IFN responses, were not reported to suffer from severe influenza (Glocker et al., 2009; Begue et al., 2011; Boisson-Dupuis et al., 2012; Hambleton et al., 2013; Duncan et al., 2015; Kreins et al., 2015; Shahni et al., 2015; Eletto et al., 2016; Moens et al., 2017) . Moreover, patients with any of the >350 other known inborn errors of immunity, including patients lacking T cells, or B cells, or both, have not been reported to suffer from severe influenza Picard et al., 2018) . Collectively, these data suggest that the human GATA2-and IRF7-dependent production of type I and/or type III IFNs is essential for protective immunity against influenza virus.