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

Among patients with defects in the type I and/or III IFN signaling pathways, complications from MMR vaccine have been reported in patients with IFN AR2, STAT1, or STAT2 bi-allelic mutations (Hambleton et al., 2013; Duncan et al., 2015; Burns et al., 2016; Moens et al., 2017) . Although relatively rare in STAT1-deficient individuals, a vaccine-strain MMR infection was reported in the only individual with AR complete STAT1 deficiency who was vaccinated . It is unclear whether patients with STAT2 and IFN AR2 deficiency have a complete or partial deficiency (Hambleton et al., 2013; Duncan et al., 2015; Moens et al., 2017) . Interestingly, MMR vaccine complications were not observed in patients with AR partial STAT1 deficiency, nor have they been reported in patients with partial JAK1 or complete TYK2 deficiency who were vaccinated (Boisson-Dupuis et al., 2012; Kreins et al., 2015; Eletto et al., 2016) . This suggests a possible divergence from mice, where STAT1 is dispensable but STAT2 is not, for protection against measles virus (Hahm et al., 2005; O'Donnell et al., 2012) . The most parsimonious theory explaining these observations is that STAT2 and IRF9 mediate a physiologically relevant branch of the type I and III IFN signaling pathway in mice independently of STAT1, while some subset of this branch is dependent on STAT1 signaling in humans. STAT2-IRF9 complexes have been described in both mice and humans, but it is unclear if they could drive the cellular changes required for defense against viral infection (Lou et al., 2009; Abdul-Sater et al., 2015) . Of note, in our mRNA-seq analysis, we observed up-regulation of STAT2 in P's primary fibroblasts and B-LCL in response to IFN-α2b stimulation in vitro, perhaps not coincidentally and consistent with nonredundant roles for STAT2 and IRF9 in immunity to measles infection (Hambleton et al., 2013) . These results add to evidence in mice that the different components of the ISGF3 complex regulate distinct, nonredundant subsets of ISGs in addition to a jointly regulated core of genes . Alternatively, the different MMR phenotypes in patients with various inborn errors of type I and III IFN immunity may merely reflect the impact of modifiers or of the environment itself, including the MMR inoculum. Ultimately, the experiment of nature deciphered in this report reveals the nonredundant roles of human IRF9 in the type I and/or III IFN signaling pathways for cell-intrinsic immunity against influenza virus and probably also the MMR vaccine.