Science DOI: 10.1126/science.aaa1578
Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency
Abstract
Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient?s leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient?s dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.
- Report
Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency
- Michael J. Ciancanelli1,
- Sarah X. L. Huang2,3,*,
- Priya Luthra4,*,
- Hannah Garner5,*,
- Yuval Itan1,
- Stefano Volpi6,7,
- Fabien G. Lafaille1,
- C?line Trouillet5,
- Mirco Schmolke4,
- Randy A. Albrecht4,8,
- Elisabeth Israelsson9,
- Hye Kyung Lim1,
- Melina Casadio1,
- Tamar Hermesh1,
- Lazaro Lorenzo10,11,
- Lawrence W. Leung4,
- Vincent Pedergnana10,11,
- Bertrand Boisson1,
- Satoshi Okada1,12,
- Capucine Picard1,10,11,13,
- Benedicte Ringuier14,
- Fran?oise Troussier15,
- Damien Chaussabel9,16,?,
- Laurent Abel1,10,11,?,
- Isabelle Pellier17,?,
- Luigi D. Notarangelo6,?,
- Adolfo Garc?a-Sastre4,8,18,?,
- Christopher F. Basler4,?,
- Fr?d?ric Geissmann5,?,
- Shen-Ying Zhang1,10,11,?,
- Hans-Willem Snoeck2,3,?,
- Jean-Laurent Casanova1,10,11,19,20,?
Abstract
Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient?s leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient?s dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.