Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
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MOSAIC Study was supported by a joint award from the Wellcome Trust and the Medical Research Council (090382/Z/09/Z). We gratefully acknowledge the support of the MOSAIC administrative team (M. Cross, L.-A. Cumming, M. Minns, T. Ford, B. Cerutti, D. Gardner and Z. Williams) and the generosity of our patients and their families, healthy volunteers, and staff at participating National Health Service (NHS) hospitals (Alder Hey Children's Hospital; Brighton & Sussex University Hospitals NHS Trust; Central Manchester University Hospitals NHS Foundation Trust; Chelsea and Westminster Hospital NHS Foundation Trust; 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; University Hospitals Coventry and Warwickshire NHS Trust). In particular, we thank K. Alshafi, S. Ashton, E. Bailey, A. Bermingham, M. Berry, C. Bloom, A. Booth, E. Brannigan, S. Bremang, J. Clark, 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, 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 and F. Wurie. We also thank E. Anguiano and members of the Genomic Core, BIIR, Dallas, for assistance with the microarray analysis; and M. Berry for guidance. We especially thank the MOSAIC Data Team (L. Drumright, L. Garcia-Alvarez, J. Lieber, S. Mookerjee and B. Pamba) for assistance in collating and validating clinical data; R. Smyth for careful review of the manuscript; and K. Strimmer for statistical advice in revisions of the manuscript. F. Rozakeas helped with recruiting samples from all the healthy control subjects at NIMR (Mill Hill). The MOSAIC consortium (ClinicalTrials.gov identifier NCT00965354) was supported by UK National Institute for Health Research (NIHR) Comprehensive Local Research Networks (CLRNs), the Biomedical Research Centre (NIHR Imperial BRC) and Unit (NIHR Liverpool BRU), the Health Protection Research Unit in Respiratory Infections in partnership with Public Health England (PHE) at Imperial College London (NIHR HPRU RI), the Health Protection Agency (latterly PHE) Microbiology Services, Colindale and the staff of the Roslin Institute, Edinburgh, Scotland. A.O.G. and C.G. were supported by the Medical Research Council, United Kingdom (U117565642), The Francis Crick Institute, London (AOG10126, which receives its core funding from Cancer Research UK (FC001126)), the UK Medical Research Council (FC001126), the Wellcome Trust (FC001126) and the UK Medical Research Council (MR/U117565642/1). S.B. was in part jointly funded by the UK Medical Research Council (MRC) as above and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (MR/J010723/1). C.B. was funded by an MRC CRTF. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, Public Health England or the Department of Health (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Maximillian S. Habibi, Sebastian L. Johnston, Trevor T. Hansel, Mike Levin, Ryan S. Thwaites, John O. Warner, William O. Cookson, Brian G. Gazzard, Alan Hay, John McCauley, Paul Aylin, Deborah Ashby, Wendy S. Barclay, R. A. Elderfield, Simon Nadel, Jethro A. Herberg, Lydia N. Drumright, Laura Garcia-Alvarez, Alison H. Holmes, Onn M. Kon, Stephen J. Aston, Stephen B. Gordon, Tracy Hussell, Catherine Thompson, Maria C. Zambon, Kenneth J. Baillie, David A. Hume, Peter Simmonds, Andrew Hayward, Rosalind L. Smyth, Paul S. McNamara, Malcolm G. Semple, Jonathan S. Nguyen-Van-Tam, Ling-Pei Ho, Andrew J. McMichael, Paul Kellam, Walt E Adamson, William F Carman and Mark J. Griffiths