IFITM3 restricts the morbidity and mortality associated with influenza

Aaron R. Everitt; Simon Clare; Thomas Pertel; Sinu P. John; Rachael S. Wash; Sarah E. Smith; Christopher R. Chin; Eric M. Feeley; Jennifer S. Sims; David J. Adams; Helen M. Wise; Leanne Kane; David Goulding; Paul Digard; Verneri Anttila; J. Kenneth Baillie; Tim S. Walsh; David A. Hume; Aarno Palotie; Yali Xue; Vincenza Colonna; Chris Tyler-Smith; Jake Dunning; Stephen B. Gordon; Rosalind L. Smyth; Peter J. Openshaw; Gordon Dougan; Abraham L. Brass; Paul Kellam; K. Everingham; H. Dawson; D. Hope; P. Ramsay; A. Campbell; S. Kerr; D. Harrison; K. Rowan; J. Addison; N. Donald; S. Galt; D. Noble; J. Taylor; N. Webster; I. Taylor; J. Aldridge; R. Dornan; C. Richard; D. Gilmour; R. Simmons; R. White; C. Jardine; D. Williams; M. Booth; T. Quasim; V. Watson; P. Henry; F. Munro; L. Bell; J. Ruddy; S. Cole; J. Southward; P. Allcoat; S. Gray; M. McDougall; J. Matheson; J. Whiteside; D. Alcorn; K. Rooney; R. Sundaram; G. Imrie; J. Bruce; K. McGuigan; S. Moultrie; C. Cairns; J. Grant; M. Hughes; C. Murdoch; A. Davidson; G. Harris; R. Paterson; C. Wallis; S. Binning; M. Pollock; J. Antonelli; A. Duncan; J. Gibson; C. McCulloch; L. Murphy; C. Haley; G. Faulkner; T. Freeman; D. Chaussabel; W. E. Adamson; W. F. Carman; C. Thompson; M. C. Zambon; P. Aylin; D. Ashby; W. S. Barclay; S. J. Brett; W. O. Cookson; L. N. Drumright; R. A. Elderfield; L. Garcia-Alvarez; B. G. Gazzard; M. J. Griffiths; M. S. Habibi; T. T. Hansel; J. A. Herberg; A. H. Holmes; T. Hussell; S. L. Johnston; O. M. Kon; M. Levin; M. F. Moffatt; S. Nadel; J. O. Warner; S. J. Aston; A. Hay; J. McCauley; A. O'Garra; J. Banchereau; A. Hayward; P. Simmonds; P. S. McNamara; M. G. Semple; J. S. Nguyen-Van-Tam; L. P. Ho; A. J. McMichael

doi:10.1038/nature10921

IFITM3 restricts the morbidity and mortality associated with influenza

Aaron R. Everitt, Simon Clare, Thomas Pertel, Sinu P. John, Rachael S. Wash, Sarah E. Smith, Christopher R. Chin, Eric M. Feeley, Jennifer S. Sims, David J. Adams, Helen M. Wise, Leanne Kane, David Goulding, Paul Digard, Verneri Anttila, J. Kenneth Baillie, Tim S. Walsh, David A. Hume, Aarno Palotie, Yali XueVincenza Colonna, Chris Tyler-Smith, Jake Dunning, Stephen B. Gordon, Rosalind L. Smyth, Peter J. Openshaw, Gordon Dougan, Abraham L. Brass, Paul Kellam^*, K. Everingham, H. Dawson, D. Hope, P. Ramsay, A. Campbell, S. Kerr, D. Harrison, K. Rowan, J. Addison, N. Donald, S. Galt, D. Noble, J. Taylor, N. Webster, I. Taylor, J. Aldridge, R. Dornan, C. Richard, D. Gilmour, R. Simmons, R. White, C. Jardine, D. Williams, M. Booth, T. Quasim, V. Watson, P. Henry, F. Munro, L. Bell, J. Ruddy, S. Cole, J. Southward, P. Allcoat, S. Gray, M. McDougall, J. Matheson, J. Whiteside, D. Alcorn, K. Rooney, R. Sundaram, G. Imrie, J. Bruce, K. McGuigan, S. Moultrie, C. Cairns, J. Grant, M. Hughes, C. Murdoch, A. Davidson, G. Harris, R. Paterson, C. Wallis, S. Binning, M. Pollock, J. Antonelli, A. Duncan, J. Gibson, C. McCulloch, L. Murphy, C. Haley, G. Faulkner, T. Freeman, D. Chaussabel, W. E. Adamson, W. F. Carman, C. Thompson, M. C. Zambon, P. Aylin, D. Ashby, W. S. Barclay, S. J. Brett, W. O. Cookson, L. N. Drumright, R. A. Elderfield, L. Garcia-Alvarez, B. G. Gazzard, M. J. Griffiths, M. S. Habibi, T. T. Hansel, J. A. Herberg, A. H. Holmes, T. Hussell, S. L. Johnston, O. M. Kon, M. Levin, M. F. Moffatt, S. Nadel, J. O. Warner, S. J. Aston, A. Hay, J. McCauley, A. O'Garra, J. Banchereau, A. Hayward, P. Simmonds, P. S. McNamara, M. G. Semple, J. S. Nguyen-Van-Tam, L. P. Ho, A. J. McMichael

^*Corresponding author for this work

Respiratory Virus Unit

Research output: Contribution to journal › Article › peer-review

621 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	519-523
Number of pages	5
Journal	Nature
Volume	484
Issue number	7395
DOIs	https://doi.org/10.1038/nature10921
Publication status	Published - 26 Apr 2012

Bibliographical note

Funding Information:
Acknowledgements We would like to thank C. Brandt for maintaining mouse colony health and well-being and T. Hussell for provision of A/X-31 virus. We also thank D. Gurdasani and M. Sandhu for statistical analysis of genotype frequencies. We also thank M. Hu and I. Gallego Romero for calculating genome-wide selection statistics. This work was supported by the Wellcome Trust. The MOSAIC work was supported by Imperial’s Comprehensive Biomedical Research Centre (cBRC), the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK. The GenISIS work was supported by the Chief Scientist Office (Scotland). A.L.B. is the recipient of a Charles H. Hood Foundation Child Health Research Award, and is supported by grants from the Phillip T. and Susan M. Ragon Institute Foundation, the Bill and Melinda Gates Foundation’s Global Health Program and the National Institute of Allergy and Infectious Diseases (R01AI091786). J.K.B. is supported by a Wellcome Trust Clinical Lectureship (090385/Z/09/Z) through the Edinburgh Clinical Academic Track (ECAT). We acknowledge the assistance of K. Alshafi, E. Bailey, A. Bermingham, M. Berry, C. Bloom, E. Brannigan, S. Bremang, J. Clark, M. C. Cox, M. Cross, L. A. Cumming, S. Dyas, J. England-Smith, J. Enstone, D. Ferreira, N. Goddard, A. Godlee, S. Gormley, M. Guiver, M. O. Hassan-Ibrahim, H. Hill, P. Holloway, K. Hoschler, G. Houghton, F. Hughes, R. R. Israel, A. Jepson, K. D. Jones, W. P. Kelleher, M. Kidd, K. Knox, A. Lackenby, G. Lloyd, H. Longworth, M. Minns, S. Mookerjee, S. Mt-Isa, D. Muir, A. Paras, V. Pascual, L. Rae, S. Rodenhurst, F. Rozakeas, E. Scott, E. Sergi, N. Shah, V. Sutton, J. Vernazza, A. W. Walker, C. Wenden, T. Wotherspoon, A. D. Wright, F. Wurie and the clinical and laboratory staff of the Alder Hey Children’s NHS Foundation Trust, Brighton & Sussex University Hospitals NHS Trust, Central Manchester University Hospitals NHS Foundation Trust, Chelsea and Westminster Hospital NHS Foundation Trust, Alder Hey Children’s Hospital and Liverpool School of Tropical Medicine, Health Protection Agency Microbiology Services Colindale, Imperial College Healthcare NHS Trust, Liverpool Women’s NHS Foundation Trust, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Royal Brompton and Harefield NHS Foundation Trust, The Roslin Institute, Edinburgh, University Hospitals Coventry and Warwickshire NHS Trust. The MOSAIC consortium was supported by several Comprehensive Local Research Networks (CLRNs), the National Institute for Health Research (NIHR), UK, and by the Biomedical Research Centre (BRC) and Unit (BRU) funds. Finally, we thank all patients and their relatives for their generous agreement to inclusion in this study.

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Cite this

Everitt, A. R., Clare, S., Pertel, T., John, S. P., Wash, R. S., Smith, S. E., Chin, C. R., Feeley, E. M., Sims, J. S., Adams, D. J., Wise, H. M., Kane, L., Goulding, D., Digard, P., Anttila, V., Baillie, J. K., Walsh, T. S., Hume, D. A., Palotie, A., ... McMichael, A. J. (2012). IFITM3 restricts the morbidity and mortality associated with influenza. Nature, 484(7395), 519-523. https://doi.org/10.1038/nature10921

@article{f79cb23cb6e34d9ba577fd42a312da1f,

title = "IFITM3 restricts the morbidity and mortality associated with influenza",

abstract = "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.",

author = "Everitt, {Aaron R.} and Simon Clare and Thomas Pertel and John, {Sinu P.} and Wash, {Rachael S.} and Smith, {Sarah E.} and Chin, {Christopher R.} and Feeley, {Eric M.} and Sims, {Jennifer S.} and Adams, {David J.} and Wise, {Helen M.} and Leanne Kane and David Goulding and Paul Digard and Verneri Anttila and Baillie, {J. Kenneth} and Walsh, {Tim S.} and Hume, {David A.} and Aarno Palotie and Yali Xue and Vincenza Colonna and Chris Tyler-Smith and Jake Dunning and Gordon, {Stephen B.} and Smyth, {Rosalind L.} and Openshaw, {Peter J.} and Gordon Dougan and Brass, {Abraham L.} and Paul Kellam and K. Everingham and H. Dawson and D. Hope and P. Ramsay and A. Campbell and S. Kerr and D. Harrison and K. Rowan and J. Addison and N. Donald and S. Galt and D. Noble and J. Taylor and N. Webster and I. Taylor and J. Aldridge and R. Dornan and C. Richard and D. Gilmour and R. Simmons and R. White and C. Jardine and D. Williams and M. Booth and T. Quasim and V. Watson and P. Henry and F. Munro and L. Bell and J. Ruddy and S. Cole and J. Southward and P. Allcoat and S. Gray and M. McDougall and J. Matheson and J. Whiteside and D. Alcorn and K. Rooney and R. Sundaram and G. Imrie and J. Bruce and K. McGuigan and S. Moultrie and C. Cairns and J. Grant and M. Hughes and C. Murdoch and A. Davidson and G. Harris and R. Paterson and C. Wallis and S. Binning and M. Pollock and J. Antonelli and A. Duncan and J. Gibson and C. McCulloch and L. Murphy and C. Haley and G. Faulkner and T. Freeman and D. Chaussabel and Adamson, {W. E.} and Carman, {W. F.} and C. Thompson and Zambon, {M. C.} and P. Aylin and D. Ashby and Barclay, {W. S.} and Brett, {S. J.} and Cookson, {W. O.} and Drumright, {L. N.} and Elderfield, {R. A.} and L. Garcia-Alvarez and Gazzard, {B. G.} and Griffiths, {M. J.} and Habibi, {M. S.} and Hansel, {T. T.} and Herberg, {J. A.} and Holmes, {A. H.} and T. Hussell and Johnston, {S. L.} and Kon, {O. M.} and M. Levin and Moffatt, {M. F.} and S. Nadel and Warner, {J. O.} and Aston, {S. J.} and A. Hay and J. McCauley and A. O'Garra and J. Banchereau and A. Hayward and P. Simmonds and McNamara, {P. S.} and Semple, {M. G.} and Nguyen-Van-Tam, {J. S.} and Ho, {L. P.} and McMichael, {A. J.}",

note = "Funding Information: Acknowledgements We would like to thank C. Brandt for maintaining mouse colony health and well-being and T. Hussell for provision of A/X-31 virus. We also thank D. Gurdasani and M. Sandhu for statistical analysis of genotype frequencies. We also thank M. Hu and I. Gallego Romero for calculating genome-wide selection statistics. This work was supported by the Wellcome Trust. The MOSAIC work was supported by Imperial{\textquoteright}s Comprehensive Biomedical Research Centre (cBRC), the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK. The GenISIS work was supported by the Chief Scientist Office (Scotland). A.L.B. is the recipient of a Charles H. Hood Foundation Child Health Research Award, and is supported by grants from the Phillip T. and Susan M. Ragon Institute Foundation, the Bill and Melinda Gates Foundation{\textquoteright}s Global Health Program and the National Institute of Allergy and Infectious Diseases (R01AI091786). J.K.B. is supported by a Wellcome Trust Clinical Lectureship (090385/Z/09/Z) through the Edinburgh Clinical Academic Track (ECAT). We acknowledge the assistance of K. Alshafi, E. Bailey, A. Bermingham, M. Berry, C. Bloom, E. Brannigan, S. Bremang, J. Clark, M. C. Cox, M. Cross, L. A. Cumming, S. Dyas, J. England-Smith, J. Enstone, D. Ferreira, N. Goddard, A. Godlee, S. Gormley, M. Guiver, M. O. Hassan-Ibrahim, H. Hill, P. Holloway, K. Hoschler, G. Houghton, F. Hughes, R. R. Israel, A. Jepson, K. D. Jones, W. P. Kelleher, M. Kidd, K. Knox, A. Lackenby, G. Lloyd, H. Longworth, M. Minns, S. Mookerjee, S. Mt-Isa, D. Muir, A. Paras, V. Pascual, L. Rae, S. Rodenhurst, F. Rozakeas, E. Scott, E. Sergi, N. Shah, V. Sutton, J. Vernazza, A. W. Walker, C. Wenden, T. Wotherspoon, A. D. Wright, F. Wurie and the clinical and laboratory staff of the Alder Hey Children{\textquoteright}s NHS Foundation Trust, Brighton & Sussex University Hospitals NHS Trust, Central Manchester University Hospitals NHS Foundation Trust, Chelsea and Westminster Hospital NHS Foundation Trust, Alder Hey Children{\textquoteright}s Hospital and Liverpool School of Tropical Medicine, Health Protection Agency Microbiology Services Colindale, Imperial College Healthcare NHS Trust, Liverpool Women{\textquoteright}s NHS Foundation Trust, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Royal Brompton and Harefield NHS Foundation Trust, The Roslin Institute, Edinburgh, University Hospitals Coventry and Warwickshire NHS Trust. The MOSAIC consortium was supported by several Comprehensive Local Research Networks (CLRNs), the National Institute for Health Research (NIHR), UK, and by the Biomedical Research Centre (BRC) and Unit (BRU) funds. Finally, we thank all patients and their relatives for their generous agreement to inclusion in this study.",

year = "2012",

month = apr,

day = "26",

doi = "10.1038/nature10921",

language = "English",

volume = "484",

pages = "519--523",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7395",

}

Everitt, AR, Clare, S, Pertel, T, John, SP, Wash, RS, Smith, SE, Chin, CR, Feeley, EM, Sims, JS, Adams, DJ, Wise, HM, Kane, L, Goulding, D, Digard, P, Anttila, V, Baillie, JK, Walsh, TS, Hume, DA, Palotie, A, Xue, Y, Colonna, V, Tyler-Smith, C, Dunning, J, Gordon, SB, Smyth, RL, Openshaw, PJ, Dougan, G, Brass, AL, Kellam, P, Everingham, K, Dawson, H, Hope, D, Ramsay, P, Campbell, A, Kerr, S, Harrison, D, Rowan, K, Addison, J, Donald, N, Galt, S, Noble, D, Taylor, J, Webster, N, Taylor, I, Aldridge, J, Dornan, R, Richard, C, Gilmour, D, Simmons, R, White, R, Jardine, C, Williams, D, Booth, M, Quasim, T, Watson, V, Henry, P, Munro, F, Bell, L, Ruddy, J, Cole, S, Southward, J, Allcoat, P, Gray, S, McDougall, M, Matheson, J, Whiteside, J, Alcorn, D, Rooney, K, Sundaram, R, Imrie, G, Bruce, J, McGuigan, K, Moultrie, S, Cairns, C, Grant, J, Hughes, M, Murdoch, C, Davidson, A, Harris, G, Paterson, R, Wallis, C, Binning, S, Pollock, M, Antonelli, J, Duncan, A, Gibson, J, McCulloch, C, Murphy, L, Haley, C, Faulkner, G, Freeman, T, Chaussabel, D, Adamson, WE, Carman, WF, Thompson, C , Zambon, MC, Aylin, P, Ashby, D, Barclay, WS, Brett, SJ, Cookson, WO, Drumright, LN, Elderfield, RA, Garcia-Alvarez, L, Gazzard, BG, Griffiths, MJ, Habibi, MS, Hansel, TT, Herberg, JA, Holmes, AH, Hussell, T, Johnston, SL, Kon, OM, Levin, M, Moffatt, MF, Nadel, S, Warner, JO, Aston, SJ, Hay, A, McCauley, J, O'Garra, A, Banchereau, J, Hayward, A, Simmonds, P, McNamara, PS, Semple, MG, Nguyen-Van-Tam, JS, Ho, LP & McMichael, AJ 2012, 'IFITM3 restricts the morbidity and mortality associated with influenza', Nature, vol. 484, no. 7395, pp. 519-523. https://doi.org/10.1038/nature10921

TY - JOUR

T1 - IFITM3 restricts the morbidity and mortality associated with influenza

AU - Everitt, Aaron R.

AU - Clare, Simon

AU - Pertel, Thomas

AU - John, Sinu P.

AU - Wash, Rachael S.

AU - Smith, Sarah E.

AU - Chin, Christopher R.

AU - Feeley, Eric M.

AU - Sims, Jennifer S.

AU - Adams, David J.

AU - Wise, Helen M.

AU - Kane, Leanne

AU - Goulding, David

AU - Digard, Paul

AU - Anttila, Verneri

AU - Baillie, J. Kenneth

AU - Walsh, Tim S.

AU - Hume, David A.

AU - Palotie, Aarno

AU - Xue, Yali

AU - Colonna, Vincenza

AU - Tyler-Smith, Chris

AU - Dunning, Jake

AU - Gordon, Stephen B.

AU - Smyth, Rosalind L.

AU - Openshaw, Peter J.

AU - Dougan, Gordon

AU - Brass, Abraham L.

AU - Kellam, Paul

AU - Everingham, K.

AU - Dawson, H.

AU - Hope, D.

AU - Ramsay, P.

AU - Campbell, A.

AU - Kerr, S.

AU - Harrison, D.

AU - Rowan, K.

AU - Addison, J.

AU - Donald, N.

AU - Galt, S.

AU - Noble, D.

AU - Taylor, J.

AU - Webster, N.

AU - Taylor, I.

AU - Aldridge, J.

AU - Dornan, R.

AU - Richard, C.

AU - Gilmour, D.

AU - Simmons, R.

AU - White, R.

AU - Jardine, C.

AU - Williams, D.

AU - Booth, M.

AU - Quasim, T.

AU - Watson, V.

AU - Henry, P.

AU - Munro, F.

AU - Bell, L.

AU - Ruddy, J.

AU - Cole, S.

AU - Southward, J.

AU - Allcoat, P.

AU - Gray, S.

AU - McDougall, M.

AU - Matheson, J.

AU - Whiteside, J.

AU - Alcorn, D.

AU - Rooney, K.

AU - Sundaram, R.

AU - Imrie, G.

AU - Bruce, J.

AU - McGuigan, K.

AU - Moultrie, S.

AU - Cairns, C.

AU - Grant, J.

AU - Hughes, M.

AU - Murdoch, C.

AU - Davidson, A.

AU - Harris, G.

AU - Paterson, R.

AU - Wallis, C.

AU - Binning, S.

AU - Pollock, M.

AU - Antonelli, J.

AU - Duncan, A.

AU - Gibson, J.

AU - McCulloch, C.

AU - Murphy, L.

AU - Haley, C.

AU - Faulkner, G.

AU - Freeman, T.

AU - Chaussabel, D.

AU - Adamson, W. E.

AU - Carman, W. F.

AU - Thompson, C.

AU - Zambon, M. C.

AU - Aylin, P.

AU - Ashby, D.

AU - Barclay, W. S.

AU - Brett, S. J.

AU - Cookson, W. O.

AU - Drumright, L. N.

AU - Elderfield, R. A.

AU - Garcia-Alvarez, L.

AU - Gazzard, B. G.

AU - Griffiths, M. J.

AU - Habibi, M. S.

AU - Hansel, T. T.

AU - Herberg, J. A.

AU - Holmes, A. H.

AU - Hussell, T.

AU - Johnston, S. L.

AU - Kon, O. M.

AU - Levin, M.

AU - Moffatt, M. F.

AU - Nadel, S.

AU - Warner, J. O.

AU - Aston, S. J.

AU - Hay, A.

AU - McCauley, J.

AU - O'Garra, A.

AU - Banchereau, J.

AU - Hayward, A.

AU - Simmonds, P.

AU - McNamara, P. S.

AU - Semple, M. G.

AU - Nguyen-Van-Tam, J. S.

AU - Ho, L. P.

AU - McMichael, A. J.

N1 - Funding Information: Acknowledgements We would like to thank C. Brandt for maintaining mouse colony health and well-being and T. Hussell for provision of A/X-31 virus. We also thank D. Gurdasani and M. Sandhu for statistical analysis of genotype frequencies. We also thank M. Hu and I. Gallego Romero for calculating genome-wide selection statistics. This work was supported by the Wellcome Trust. The MOSAIC work was supported by Imperial’s Comprehensive Biomedical Research Centre (cBRC), the Wellcome Trust (090382/Z/09/Z) and Medical Research Council UK. The GenISIS work was supported by the Chief Scientist Office (Scotland). A.L.B. is the recipient of a Charles H. Hood Foundation Child Health Research Award, and is supported by grants from the Phillip T. and Susan M. Ragon Institute Foundation, the Bill and Melinda Gates Foundation’s Global Health Program and the National Institute of Allergy and Infectious Diseases (R01AI091786). J.K.B. is supported by a Wellcome Trust Clinical Lectureship (090385/Z/09/Z) through the Edinburgh Clinical Academic Track (ECAT). We acknowledge the assistance of K. Alshafi, E. Bailey, A. Bermingham, M. Berry, C. Bloom, E. Brannigan, S. Bremang, J. Clark, M. C. Cox, M. Cross, L. A. Cumming, S. Dyas, J. England-Smith, J. Enstone, D. Ferreira, N. Goddard, A. Godlee, S. Gormley, M. Guiver, M. O. Hassan-Ibrahim, H. Hill, P. Holloway, K. Hoschler, G. Houghton, F. Hughes, R. R. Israel, A. Jepson, K. D. Jones, W. P. Kelleher, M. Kidd, K. Knox, A. Lackenby, G. Lloyd, H. Longworth, M. Minns, S. Mookerjee, S. Mt-Isa, D. Muir, A. Paras, V. Pascual, L. Rae, S. Rodenhurst, F. Rozakeas, E. Scott, E. Sergi, N. Shah, V. Sutton, J. Vernazza, A. W. Walker, C. Wenden, T. Wotherspoon, A. D. Wright, F. Wurie and the clinical and laboratory staff of the Alder Hey Children’s NHS Foundation Trust, Brighton & Sussex University Hospitals NHS Trust, Central Manchester University Hospitals NHS Foundation Trust, Chelsea and Westminster Hospital NHS Foundation Trust, Alder Hey Children’s Hospital and Liverpool School of Tropical Medicine, Health Protection Agency Microbiology Services Colindale, Imperial College Healthcare NHS Trust, Liverpool Women’s NHS Foundation Trust, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Royal Brompton and Harefield NHS Foundation Trust, The Roslin Institute, Edinburgh, University Hospitals Coventry and Warwickshire NHS Trust. The MOSAIC consortium was supported by several Comprehensive Local Research Networks (CLRNs), the National Institute for Health Research (NIHR), UK, and by the Biomedical Research Centre (BRC) and Unit (BRU) funds. Finally, we thank all patients and their relatives for their generous agreement to inclusion in this study.

PY - 2012/4/26

Y1 - 2012/4/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84862777209&partnerID=8YFLogxK

U2 - 10.1038/nature10921

DO - 10.1038/nature10921

M3 - Article

C2 - 22446628

AN - SCOPUS:84862777209

SN - 0028-0836

VL - 484

SP - 519

EP - 523

JO - Nature

JF - Nature

IS - 7395

ER -

IFITM3 restricts the morbidity and mortality associated with influenza

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