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

We herein describe AR, complete IRF9 deficiency in a child with life-threatening influenza. Our data establish a causal relationship between IRF9 deficiency and this patient's severe pulmonary influenza (Casanova et al., 2014) . Following autosomal dominant GATA2 deficiency and AR IRF7 deficiency, AR IRF9 deficiency is the third described single-gene inborn error of immunity that can underlie life-threatening influenza pneumonitis (Casanova, 2015a,b; Ciancanelli et al., 2016) . In contrast to IRF7 deficiency, which disrupts the amplification of antiviral IFNs, especially in pDCs, which are the only cells expressing high constitutive levels of IRF7 , IRF9 deficiency results in an inability of all cell types to respond fully and effectively to type I IFNs, and by inference type III IFNs. The mechanistic connection between IRF7 and IRF9 deficiency in humans suggests that the type I and III IFN responses driven by IRF7 amplification and mediated by IRF9 signaling are essential for defense against influenza virus. However, patients with other defects in type I and/or III IFN signaling pathway, including deficiency of STAT1, STAT2, JAK1, TYK2, IFN AR2, and IL10RB, have not been reported to have suffered from severe influenza (Boisson-Dupuis et al., 2012; Hambleton et al., 2013; Engelhardt and Grimbacher, 2014; Duncan et al., 2015; Kreins et al., 2015; Shahni et al., 2015; Eletto et al., 2016; Moens et al., 2017) . This is perhaps because (1) they died of other severe infections before exposure to influenza virus, (2) the virus can be controlled independently of these signaling proteins, (3) at least some type I IFNs can signal without these proteins (de Weerd et al., 2013) , or (4) the defect is partial, as opposed to complete, due to the hypomorphic nature of some mutant alleles (Chapgier et al., 2006; Hambleton et al., 2013; Duncan et al., 2015) . Alternatively, IRF9 and IRF7, unlike the other five genes, might regulate transcription of a key subset of ISGs that specifically mediate immunity to influenza virus following type I and III IFN stimulation. A patient with IFN AR1 deficiency was recently reported, yet his additional defect of IFN GR2 prevents conclusions to be drawn as to the mechanism of infectious phenotypes (Hoyos-Bachiloglu et al., 2017) . A clearer picture of the contributions of these genes to human protective immunity to influenza virus will emerge as more inborn errors are discovered and as more patients are diagnosed.