title: Host genetics of severe influenza: from mouse Mx1 to human IRF7.
abstract: Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The crucial role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-α/β-inducible Mx1 as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the in vivo role of other mouse genes involved in IFN-α/β and -λ immunity. A series of in vitro studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN-α/β- and IFN-λ-dependent protective immunity against primary influenza in vivo, as inferred from a patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza.
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. Electronic address: mici751@rockefeller.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciancanelli
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France.
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Howard Hughes Medical Institute, New York, NY, USA; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D016867:Immunocompromised Host; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D064547:Myxovirus Resistance Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009975:Orthomyxoviridae / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D016207:Cytokines; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D016899:Interferon-beta; D064547:Myxovirus Resistance Proteins; C494234:IRF7 protein, human; C579070:Mx1 protein, mouse; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda