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Updated: Mar 27, 2026
Co-immunoprecipitation of the Mouse Mx1 Protein with the Influenza A Virus Nucleoprotein
Published on: April 21, 2015
Host genetics of severe influenza: from mouse Mx1 to human IRF7
Michael J Ciancanelli1, Laurent Abel2, Shen-Ying Zhang2
1St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
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.
Insights
Host genetics significantly influence influenza severity. A deficiency in Interferon Regulatory Factor 7 (IRF7) was linked to life-threatening influenza, highlighting its critical role in protective immunity.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Influenza typically causes mild illness, but severe cases suggest underlying host genetic factors.
- While viral virulence explains population-level differences, individual variability in influenza severity remains poorly understood.
- Previous studies identified mouse genes like Mx1 and those in interferon pathways as crucial for influenza immunity.
Purpose of the Study:
- To investigate the genetic basis of severe influenza in humans.
- To identify host genes critical for protective immunity against influenza viruses.
- To understand the role of interferon-dependent pathways in severe influenza outcomes.
Main Methods:
- Utilized forward and reverse genetics in mice to study influenza susceptibility genes.
- Conducted in vitro studies with mouse and human cells to elucidate cell-intrinsic protection mechanisms.
- Employed whole exome sequencing in a patient with life-threatening influenza to identify genetic defects.
Main Results:
- Mouse genetics studies identified interferon-inducible Mx1 and other IFN-α/β and -λ pathway genes.
- Human genetic studies have not yet identified significant influenza susceptibility variants.
- A patient with life-threatening influenza was found to be deficient in IRF7, an essential gene for protective immunity.
Conclusions:
- Host genetic factors, particularly IRF7, are crucial for protective immunity against severe influenza.
- Interferon-α/β and -λ signaling pathways are vital for controlling influenza infection in humans.
- Next-generation sequencing holds promise for unraveling the genetic determinants of severe influenza.
