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IFITM3 restricts the morbidity and mortality associated with influenza.
Nature. 2012 Mar 25
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18 Apr 2012
New Finding
DOI: 10.3410/f.14267190.15779439
The question of why some individuals infected with the influenza virus develop severe complications while others display only mild symptoms remains one of the most intriguing and clinically important in the field. Although a number of general factors, such as age, obesity and pregnancy, have been associated...Continue reading
The question of why some individuals infected with the influenza virus develop severe complications while others display only mild symptoms remains one of the most intriguing and clinically important in the field. Although a number of general factors, such as age, obesity and pregnancy, have been associated with the likelihood of developing complications from influenza, these factors cannot account for seemingly healthy individuals that succumb to influenza infections. In a breakthrough study, Everitt et al. find that patients hospitalized with influenza infections were 20 times more likely to carry a particular single nucleotide polymorphism (SNP) variant within the interferon-inducible transmembrane 3 (IFITM3) gene than the general population.
Known to have important antiviral function, IFITM3 has been characterized in depth in vitro. In the current study, the authors generate an IFITM3 knockout mouse and demonstrate the importance of this protein in protection against influenza infection in vivo. Analysis of the human SNP variant in vitro confirmed its deficiency in ability to control the influenza virus infection. Although this particular SNP variant was present in only 6% of hospitalized patients, this study is nevertheless important because it opens the way for identification of genetic factors associated with susceptibility to influenza and other viral infections.
Known to have important antiviral function, IFITM3 has been characterized in depth in vitro. In the current study, the authors generate an IFITM3 knockout mouse and demonstrate the importance of this protein in protection against influenza infection in vivo. Analysis of the human SNP variant in vitro confirmed its deficiency in ability to control the influenza virus infection. Although this particular SNP variant was present in only 6% of hospitalized patients, this study is nevertheless important because it opens the way for identification of genetic factors associated with susceptibility to influenza and other viral infections.
Disclosures
None declared
Add Comment
Garcia-Sastre A and Baum A: F1000Prime Recommendation of [Everitt AR et al., Nature 2012]. In F1000Prime, 18 Apr 2012; DOI: 10.3410/f.14267190.15779439. F1000Prime.com/14267190#eval15779439
18 Apr 2012
New Finding
DOI: 10.3410/f.14267190.15778159
This report provides new insights into the pathogenesis of severe viral infections. The delicate tension between the mammalian host and microbial pathogens is dramatically illustrated by syndromes of influenza infection. In humans, influenza can be relatively mild, but can also be severe and epidemic...Continue reading
This report provides new insights into the pathogenesis of severe viral infections. The delicate tension between the mammalian host and microbial pathogens is dramatically illustrated by syndromes of influenza infection. In humans, influenza can be relatively mild, but can also be severe and epidemic with devastating morbidity and mortality. Previously, these investigators identified a subgroup of interferon (IFN) effector genes that mediate cellular resistance to strains of influenza and also to other viruses including dengue and West Nile viruses {1}. They also showed that one of the IFN-inducible proteins, IFITM3, inhibits influenza A entry into the cellular cytosol from the late endocytic pathway {2}. In this report, they make a mouse knockout of Ifitm3 and find that these animals develop fulminant viral pneumonia when challenged with an influenza strain of low pathogenicity, and that protection is rescued when Ifitm3 is reintroduced.
In infected, Ifitm3-deficient mice, the fulminant pneumonia is due to exuberant viral replication and enhanced pulmonary inflammation, based on analyses of viral load, inflammatory cells, and cytokines. They also identify an allele of IFITM3 in humans that appears to be associated with hospitalization after infection with one seasonal variant of influenza A, suggesting that it predisposes to more severe disease.
In infected, Ifitm3-deficient mice, the fulminant pneumonia is due to exuberant viral replication and enhanced pulmonary inflammation, based on analyses of viral load, inflammatory cells, and cytokines. They also identify an allele of IFITM3 in humans that appears to be associated with hospitalization after infection with one seasonal variant of influenza A, suggesting that it predisposes to more severe disease.
References
Disclosures
None declared
Zimmerman G: F1000Prime Recommendation of [Everitt AR et al., Nature 2012]. In F1000Prime, 18 Apr 2012; DOI: 10.3410/f.14267190.15778159. F1000Prime.com/14267190#eval15778159
11 Jun 2012
Vincent Emery
F1000 Infectious Diseases
University of Surrey Department of Microbial and Cellular Sciences,
UK.
F1000 Infectious Diseases
University of Surrey Department of Microbial and Cellular Sciences,
UK.
Good for Teaching, New Finding
DOI: 10.3410/f.14267190.791952801
There has been significant debate over many years as to why some people cope with infections better than others. In particular, influenza can exert its effects in a mild form or in a much more severe way. While this reflects a range of factors including the genetics of the virus (genetic drift and, more importantly, genetic shift)...Continue reading
There has been significant debate over many years as to why some people cope with infections better than others. In particular, influenza can exert its effects in a mild form or in a much more severe way. While this reflects a range of factors including the genetics of the virus (genetic drift and, more importantly, genetic shift), the residual immunity in the population at risk and underlying co-morbidities, the role that host genetics plays is relatively under-investigated. This paper uses a knockout mouse model to show that the interferon-inducible transmembrane (IFITM) protein 3 is an essential defence mechanism against influenza.
When these knockout mice were challenged with influenza, they suffered a severe viral pneumonia that was similar to that observed in the devastating 1918 H1N1 Spanish influenza pandemic. The authors then went on to test whether mutations in the IFITM3 gene were associated with more severe infections, especially those requiring hospitalization during the most recent outbreaks of either seasonal or pandemic H1N1/09 influenza. A single nucleotide polymorphism (SNP) (rs12252-C) that interferes with the normal slice acceptor site within the gene encoding IFITM3 was found to be enriched in populations requiring hospitalization, compared to ethnically matched controls. In order to prove that this SNP leads to a functionally less effective IFITM3 protein, the authors introduced the mutant gene into a lung carcinoma cell line and showed that the truncated protein was unable to restrict influenza virus replication.
Looking forward, the possibility of screening for this SNP in human populations as a marker for increased risk of severe influenza infection, especially in 'at risk' populations or during times of a new pandemic, could allow a more targeted approach to the deployment of antiviral prophylaxis and treatment. For further reading, please see refs {1,2}.
When these knockout mice were challenged with influenza, they suffered a severe viral pneumonia that was similar to that observed in the devastating 1918 H1N1 Spanish influenza pandemic. The authors then went on to test whether mutations in the IFITM3 gene were associated with more severe infections, especially those requiring hospitalization during the most recent outbreaks of either seasonal or pandemic H1N1/09 influenza. A single nucleotide polymorphism (SNP) (rs12252-C) that interferes with the normal slice acceptor site within the gene encoding IFITM3 was found to be enriched in populations requiring hospitalization, compared to ethnically matched controls. In order to prove that this SNP leads to a functionally less effective IFITM3 protein, the authors introduced the mutant gene into a lung carcinoma cell line and showed that the truncated protein was unable to restrict influenza virus replication.
Looking forward, the possibility of screening for this SNP in human populations as a marker for increased risk of severe influenza infection, especially in 'at risk' populations or during times of a new pandemic, could allow a more targeted approach to the deployment of antiviral prophylaxis and treatment. For further reading, please see refs {1,2}.
References
1.
The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus.
Cell. 2009 Dec 24; 139(7): 1243-54
PMID: 20064371
DOI: 10.1016/j.cell.2009.12.017
2.
IFITM3 inhibits influenza A virus infection by preventing cytosolic entry.
PLoS Pathog. 2011 Oct; 7(10): e1002337
PMID: 22046135
DOI: 10.1371/journal.ppat.1002337
Disclosures
Vincent Emery has worked with Paul Kellam (an author of this paper) on herpesvirus-related projects and is a part of a Medical Molecular Virology centre award to University College London. Vincent Emery has not worked or published with Paul Kellam on influenza virus.
Emery V: F1000Prime Recommendation of [Everitt AR et al., Nature 2012]. In F1000Prime, 11 Jun 2012; DOI: 10.3410/f.14267190.791952801. F1000Prime.com/14267190#eval791952801
F1000Prime Recommendations, Dissents and Comments for [Everitt AR et al., Nature 2012]. In F1000Prime, 19 May 2013; F1000Prime.com/14267190
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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.
DOI: 10.1038/nature10921
PMID: 22446628
