Giuseppe
Emeritus
[Source: World Health Organization, full page: (LINK). Edited.]
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Peer-reviewed literature - 30 March 2012
IFITM3 restricts the morbidity and mortality associated with influenza
In the article published in Nature on 25th March 2012, Everitt and colleagues describe an association between a gene which codes for an interferon inducible transmembrane protein, IFITM3, and susceptibility to influenza infection [1].
The investigators used a mouse model to demonstrate that in the mice lacking IFITM3 there was increased influenza virus A(H3N2) replication in the lung tissue, whereas in control mice viral replication was limited due to the presence of IFITM3.
Further investigation of the infected mice lungs showed increased viral replication with associated substantial lung tissue damage and severe inflammation.
Further investigations into the human IFITM3 gene in 53 individuals hospitalized due to influenza A(H1N1)pdm09 or seasonal influenza in 2009-2010 indicated that 13.3% of these patients possessed variants of the gene that led to a truncated IFITM3.
In vitro investigation of cell lines carrying this gene variant confirmed that these cells were more susceptible to influenza A virus infection.
These results indicate that IFITM3 acts as a barrier to influenza virus infection in vivo and in vitro, and that in the absence of this protein, there is uncontrolled replication in the lungs and increased disease severity.
Furthermore, the enrichment of a IFITM3 variant in patients hospitalized due to influenza led authors to suggest that IFITM3-compromised individuals may be more vulnerable to the establishment and spread of influenza viruses.
Comment:
As with any infection, both host and pathogen factors play a role in the clinical severity of influenza in an individual.
In the pandemic of 2009, it was observed that while most individuals experienced mild, self-limited illness, as many as 40% of severe influenza-associated illness requiring hospital admission and a slightly lower proportion of fatal cases had no known risk factors.
The factors that increase susceptibility of individuals for severe disease have not been fully explored and likely involves more than one gene[2].
The familial clustering of severe cases of influenza A(H5N1) have often been cited as evidence of a genetic risk factors [3] and it had been previously shown that IFITM3 played a role in restricting H5N1 influenza [4], but this study extended these findings to influenza A and B associated severe illness including hospitalized patients.
Genetic variations in the virus determine its virulence, so as genetic variations of the host may also influence the course of disease. Both host and pathogen factors require further research to characterize determinants of disease severity.
Reference:
(1) Everitt, AR, Clare, S, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. doi: 10.1038/nature10921 (2012).
(2) Horby P, et al. The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review. (2012) PLoS ONE 7(3): e33180. doi:10.1371/journal.pone.0033180
(3) Horby P, et al. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? (2010) Epidemiol. Infect. doi:10.1017/S0950268810000518
(4) Feeley, E.M. et al. IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PLoS Pathog. 7, e1002337 (2011).
-IFITM3 restricts the morbidity and mortality associated with influenza
In the article published in Nature on 25th March 2012, Everitt and colleagues describe an association between a gene which codes for an interferon inducible transmembrane protein, IFITM3, and susceptibility to influenza infection [1].
The investigators used a mouse model to demonstrate that in the mice lacking IFITM3 there was increased influenza virus A(H3N2) replication in the lung tissue, whereas in control mice viral replication was limited due to the presence of IFITM3.
Further investigation of the infected mice lungs showed increased viral replication with associated substantial lung tissue damage and severe inflammation.
Further investigations into the human IFITM3 gene in 53 individuals hospitalized due to influenza A(H1N1)pdm09 or seasonal influenza in 2009-2010 indicated that 13.3% of these patients possessed variants of the gene that led to a truncated IFITM3.
In vitro investigation of cell lines carrying this gene variant confirmed that these cells were more susceptible to influenza A virus infection.
These results indicate that IFITM3 acts as a barrier to influenza virus infection in vivo and in vitro, and that in the absence of this protein, there is uncontrolled replication in the lungs and increased disease severity.
Furthermore, the enrichment of a IFITM3 variant in patients hospitalized due to influenza led authors to suggest that IFITM3-compromised individuals may be more vulnerable to the establishment and spread of influenza viruses.
Comment:
As with any infection, both host and pathogen factors play a role in the clinical severity of influenza in an individual.
In the pandemic of 2009, it was observed that while most individuals experienced mild, self-limited illness, as many as 40% of severe influenza-associated illness requiring hospital admission and a slightly lower proportion of fatal cases had no known risk factors.
The factors that increase susceptibility of individuals for severe disease have not been fully explored and likely involves more than one gene[2].
The familial clustering of severe cases of influenza A(H5N1) have often been cited as evidence of a genetic risk factors [3] and it had been previously shown that IFITM3 played a role in restricting H5N1 influenza [4], but this study extended these findings to influenza A and B associated severe illness including hospitalized patients.
Genetic variations in the virus determine its virulence, so as genetic variations of the host may also influence the course of disease. Both host and pathogen factors require further research to characterize determinants of disease severity.
Reference:
(1) Everitt, AR, Clare, S, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. doi: 10.1038/nature10921 (2012).
(2) Horby P, et al. The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review. (2012) PLoS ONE 7(3): e33180. doi:10.1371/journal.pone.0033180
(3) Horby P, et al. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? (2010) Epidemiol. Infect. doi:10.1017/S0950268810000518
(4) Feeley, E.M. et al. IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PLoS Pathog. 7, e1002337 (2011).
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