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 viruses1,2,3,4,5,6,7. 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 model8, 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’ influenza9,10. 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.

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Accessions

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

IFITM3 sequences are deposited in GenBank under the accession numbers JQ610570–JQ610621.

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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.

Author information

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK

    • Aaron R. Everitt
    • , Simon Clare
    • , Rachael S. Wash
    • , Sarah E. Smith
    • , David J. Adams
    • , Leanne Kane
    • , David Goulding
    • , Verneri Anttila
    • , Aarno Palotie
    • , Yali Xue
    • , Vincenza Colonna
    • , Chris Tyler-Smith
    • , Gordon Dougan
    •  & Paul Kellam
  2. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Charlestown, Massachusetts 02129, USA

    • Thomas Pertel
    • , Sinu P. John
    • , Christopher R. Chin
    • , Eric M. Feeley
    • , Jennifer S. Sims
    •  & Abraham L. Brass
  3. Divison of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK

    • Helen M. Wise
    •  & Paul Digard
  4. Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Roslin EH25 9RG, UK

    • J. Kenneth Baillie
    •  & David A. Hume
  5. Department of Critical Care Medicine, University of Edinburgh, Edinburgh EH16 4TJ, UK

    • J. Kenneth Baillie
    •  & Tim S. Walsh
  6. Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR), Naples, Italy

    • Vincenza Colonna
  7. Centre for Respiratory Infection, National Heart and Lung Institute, St Mary’s Campus, Imperial College London, W2 1PG, UK

    • Jake Dunning
    •  & Peter J. Openshaw
  8. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK

    • Stephen B. Gordon
  9. Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s Hospital, Liverpool L12 2AP, UK

    • Rosalind L. Smyth
  10. Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02117, USA

    • Abraham L. Brass
  11. UCL/MRC Centre for Medical Molecular Virology, Department of Infection, University College London, Cleveland Street, London W1T 4JF, UK

    • Paul Kellam
  12. Benaroya Research Institute, 1201 9th Avenue, Seattle, Washington 98101-2795, USA.

    • D. Chaussabel
  13. West of Scotland Specialist Virology Centre, Gartnavel General Hospital, Glasgow and Clyde Health Board, 1053 Great Western Road, Glasgow G12 0YN, UK.

    • W. E. Adamson
    •  & W. F. Carman
  14. Health Protection Agency, Microbiology Services Colindale, 61 Colindale Avenue, London NW9 5EQ, UK.

    • C. Thompson
    •  & M. C. Zambon
  15. Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK.

    • P. Aylin
    • , D. Ashby
    • , W. S. Barclay
    • , S. J. Brett
    • , W. O. Cookson
    • , L. N. Drumright
    • , J. Dunning
    • , 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
    • , P. J. Openshaw
    •  & J. O. Warner
  16. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.

    • S. J. Aston
    •  & S. B. Gordon
  17. National Institute for Medical Research (NIMR), The Ridgeway, London NW7 1AA, UK.

    • A. Hay
    • , J. McCauley
    •  & A. O’Garra
  18. Roche, 340 Kingsland Street, Nutley, New Jersey 07110-1199, USA.

    • J. Banchereau
  19. University College London, Gower Street, London, WC1E 6BT, UK.

    • A. Hayward
    •  & P. Kellam
  20. The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.

    • J. K. Baillie
    • , D. A. Hume
    •  & P. Simmonds
  21. Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Alder Hey Children’s Hospital, Liverpool L12 2AP, UK.

    • P. S. McNamara
    • , M. G. Semple
    •  & R. L. Smyth
  22. Epidemiology and Public Health, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK.

    • J. S. Nguyen-Van-Tam
  23. The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.

    • L.-P. Ho
    •  & A. J. McMichael
  24. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • P. Kellam
  25. Department of Critical Care Medicine, The Queen’s Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Drive, Edinburgh EH16 4TJ, UK

    • K. Everingham
    • , H. Dawson
    • , D. Hope
    • , P. Ramsay
    •  & T. S. Walsh (Local Lead Investigator)
  26. Generation Scotland, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.

    • A. Campbell
    •  & S. Kerr
  27. Intensive Care National Audit & Research Centre, Tavistock House, Tavistock Square, London WC1H 9HR, UK.

    • D. Harrison
    •  & K. Rowan
  28. Intensive Care Unit, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK.

    • J. Addison
    • , N. Donald
    • , S. Galt
    • , D. Noble
    • , J. Taylor
    •  & N. Webster (Local Lead Investigator)
  29. Intensive Care Unit, Ayr Hospital, Dallmellington Road, Ayr KA6 6DX, UK.

    • I. Taylor (Local Lead Investigator)
  30. Intensive Care Unit, Borders General Hospital, Melrose TD6 9BS, UK.

    • J. Aldridge (Local Lead Investigator)
    • , R. Dornan
    •  & C. Richard
  31. Intensive Care Unit, Crosshouse Hospital, Kilmarnock KA2 0BE, UK.

    • D. Gilmour
    • , R. Simmons (Local Lead Investigator)
    •  & R. White (Local Lead Investigator)
  32. Intensive Care Unit, Dumfries and Galloway Royal Infirmary, Dumfries DG1 4AP, UK.

    • C. Jardine
    •  & D. Williams (Local Lead Investigator)
  33. Intensive Care Unit, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.

    • M. Booth (Local Lead Investigator)
    •  & T. Quasim
  34. Intensive Care Unit, Hairmyres Hospital, Lanarkshire G75 8RG, UK.

    • V. Watson
  35. Intensive Care Unit, Inverclyde Royal Hospital, Greenock PA16 0XN, UK.

    • P. Henry
    •  & F. Munro
  36. Intensive Care Unit, Monklands Hospital, Airdrie ML6 0JS, UK.

    • L. Bell
    •  & J. Ruddy (Local Lead Investigator)
  37. Intensive Care Unit, Ninewells Hospital, Dundee DD1 9SY, UK.

    • S. Cole (Local Lead Investigator)
    •  & J. Southward
  38. Intensive Care Unit, Queen Margaret Hospital, Dunfermline KY12 0SU, UK.

    • P. Allcoat
    • , S. Gray
    •  & M. McDougall (Local Lead Investigator)
  39. Intensive Care Unit, Raigmore Hospital, Inverness IV2 3UJ, UK.

    • J. Matheson
    •  & J. Whiteside (Local Lead Investigator)
  40. Intensive Care Unit, Royal Alexandra Hospital, Paisley PA2 9PN, UK.

    • D. Alcorn
    • , K. Rooney (Local Lead Investigator)
    •  & R. Sundaram
  41. Intensive Care Unit, Southern General Hospital, Glasgow G51 4TF, UK.

    • G. Imrie (Local Lead Investigator)
  42. Intensive Care Unit, St John’s Hospital, Livingston EH54 6PP, UK.

    • J. Bruce
    • , K. McGuigan
    •  & S. Moultrie (Local Lead Investigator)
  43. Intensive Care Unit, Stirling Royal Infirmary, Stirling FK8 2AU, UK.

    • C. Cairns (Local Lead Investigator)
    • , J. Grant
    •  & M. Hughes
  44. Intensive Care Unit, Stobhill Hospital, Glasgow G21 3UW, UK.

    • C. Murdoch (Local Lead Investigator)
  45. Intensive Care Unit, Victoria Hospital, Glasgow G42 9TY, UK.

    • A. Davidson (Local Lead Investigator)
  46. Intensive Care Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.

    • G. Harris
    • , R. Paterson
    •  & C. Wallis (Local Lead Investigator)
  47. Intensive Care Unit, Western Infirmary, Glasgow G11 6NT, UK.

    • S. Binning (Local Lead Investigator)
    •  & M. Pollock
  48. Wellcome Trust Clinical Research Facility, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.

    • J. Antonelli
    • , A. Duncan
    • , J. Gibson
    • , C. McCulloch
    •  & L. Murphy
  49. Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.

    • C. Haley
    • , G. Faulkner
    • , T. Freeman
    • , D. A. Hume
    •  & J. K. Baillie (Principal Investigator)

Consortia

  1. The GenISIS Investigators

    Critical Care Medicine, University of Edinburgh

    Generation Scotland, University of Edinburgh Molecular Medicine Centre

    Intensive Care National Audit & Research Centre, London

    Intensive Care Unit, Aberdeen Royal Infirmary

    Intensive Care Unit, Ayr Hospital

    Intensive Care Unit, Borders General Hospital, Melrose

    Intensive Care Unit, Crosshouse Hospital, Kilmarnock

    Intensive Care Unit, Dumfries and Galloway Royal Infirmary

    Intensive Care Unit, Glasgow Royal Infirmary

    Intensive Care Unit, Hairmyres Hospital, Lanarkshire

    Intensive Care Unit, Inverclyde Royal Hospital, Greenock

    Intensive Care Unit, Monklands Hospital, Airdrie

    Intensive Care Unit, Ninewells Hospital, Dundee

    Intensive Care Unit, Queen Margaret Hospital, Dunfermline

    Intensive Care Unit, Raigmore Hospital, Inverness

    Intensive Care Unit, Royal Alexandra Hospital, Paisley

    Intensive Care Unit, Southern General Hospital, Glasgow

    Intensive Care Unit, St John’s Hospital, Livingston

    Intensive Care Unit, Stirling Royal Infirmary

    Intensive Care Unit, Stobhill Hospital, Glasgow

    Intensive Care Unit, Victoria Hospital, Glasgow

    Intensive Care Unit, Western General Hospital, Edinburgh

    Intensive Care Unit, Western Infirmary, Glasgow

    Wellcome Trust Clinical Research Facility, Edinburgh

    Roslin Institute, University of Edinburgh

  2. The MOSAIC Investigators

    Benaroya Research Institute, USA

    Gartnavel General Hospital, Greater Glasgow, UK

    Health Protection Agency, UK

    Imperial College London, UK

    Liverpool School of Tropical Medicine, UK

    National Institute for Medical Research, UK

    Roche, Nutley, USA

    University College London, UK

    University of Edinburgh, UK

    University of Liverpool, UK

    University of Nottingham, UK

    University of Oxford, UK

    Wellcome Trust Sanger Institute, UK

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Contributions

A.R.E., G.D., A.L.B. and P.K. designed the study; A.R.E., P.J.O., G.D., A.L.B. and P.K. wrote the manuscript; A.R.E. performed experiments and analysed data; S.C. designed experiments and performed all live animal work; S.E.S. sequenced and analysed the human Ifitm3 gene; R.S.W., S.E.S., C.R.C., J.S.S., S.P.J., T.P., E.M.F., A.L.B. and L.K. performed experiments; D.J.A. created the genetically-modified Ifitm3−/− mouse line; H.M.W. and P.D. made the influenza virus strains and advised on virology; D.G. performed microscopy; Y.X., V.C. and C.T.-S. performed positive selection analyses; V.A. and A.P. performed imputation and analysis of 1000 Genomes data; E.M.F., C.R.C. and A.L.B. performed in vitro viewRNA experiments; recruitment and selection of hospitalised individuals infected with influenza virus was co-ordinated by J.K.B., D.A.H. and T.S.W. (GenISIS) and R.L.S., S.B.G., J.D., J.K.B., D.A.H. and P.J.O. (MOSAIC).

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Abraham L. Brass or Paul Kellam.

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DOI

https://doi.org/10.1038/nature10921

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