IFITM3 restricts the morbidity and mortality associated with influenza
By Aaron Everitt, S. Clare, Thomas Pertel, S. John, R. Wash, Sarah E. Smith, Christopher R. Chin, E. Feeley, Jennifer Sims, D. Adams and 19 more. Nature, 2012
758 citations recorded by the source corpus.
The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
Subfields: Epidemiology, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/ccc169d899cd84dcb8b64142eab7a8a30049dbd7
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Citations in the corpus
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- An expression atlas of human primary cells: inference of gene function from coexpression networks (2013, background): “Additional file 6: Figure S3 shows the average expression profiles of these proposed mouse core cDC signature genes [57] across all of the human myeloid cell data sets used in the current study.”
- SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues (2020, neutral): “IFN responses that induce ISGs are essential for host antiviral defense in mice, NHP and humans (Bailey et al., 2014; Dupuis et al., 2003; Everitt et al., 2012).”
- Interferon-Stimulated Genes: A Complex Web of Host Defenses (2014, background): “This study uncovered a statistically significant enrichment for a polymorphism in the IFITM3 gene (153).”