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Science DOI: 10.1126/science.1222213
Research Article
An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response
B. W. Jagger1,2,
H. M. Wise1,*,
J. C. Kash2,
K.-A. Walters3,
N. M. Wills4,
Y.-L. Xiao2,
R. L. Dunfee2,
L. M. Schwartzman2,
A. Ozinsky3,
G. L. Bell1,?,
R. M. Dalton1,?,
A. Lo1,
S. Efstathiou1,
J. F. Atkins4,5,
A. E. Firth1,?,
J. K. Taubenberger2,?,
P. Digard1,*,?
+ Author Affiliations
1Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
2Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3Institute for Systems Biology, Seattle, WA 98109, USA.
4Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
5BioSciences Institute, University College Cork, Cork, Ireland.
+ Author Notes
↵* Present address: The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK.
↵? Present address: Cambridge Institute for Medical Research, Wellcome Trust?Medical Research Council Building, Addenbrooke?s Hospital, Hills Road, Cambridge CB2 0XY, UK.
↵? Present address: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnolog?a, Consejo Superior de Investigaciones Cient?ficas (Spanish National Research Council, CSIC), Cantoblanco, 28049 Madrid, Spain.
↵?To whom correspondence should be sent. E-mail: aef24@cam.ac.uk (A.E.F.); taubenbergerj@niaid.nih.gov (J.K.T.); paul.digard@roslin.ed.ac.uk (P.D.)
Abstract
Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame (?X-ORF?), accessed via ribosomal frameshifting. The FS product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T-lymphocyte signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.
Research Article
An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response
B. W. Jagger1,2,
H. M. Wise1,*,
J. C. Kash2,
K.-A. Walters3,
N. M. Wills4,
Y.-L. Xiao2,
R. L. Dunfee2,
L. M. Schwartzman2,
A. Ozinsky3,
G. L. Bell1,?,
R. M. Dalton1,?,
A. Lo1,
S. Efstathiou1,
J. F. Atkins4,5,
A. E. Firth1,?,
J. K. Taubenberger2,?,
P. Digard1,*,?
+ Author Affiliations
1Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
2Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3Institute for Systems Biology, Seattle, WA 98109, USA.
4Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
5BioSciences Institute, University College Cork, Cork, Ireland.
+ Author Notes
↵* Present address: The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK.
↵? Present address: Cambridge Institute for Medical Research, Wellcome Trust?Medical Research Council Building, Addenbrooke?s Hospital, Hills Road, Cambridge CB2 0XY, UK.
↵? Present address: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnolog?a, Consejo Superior de Investigaciones Cient?ficas (Spanish National Research Council, CSIC), Cantoblanco, 28049 Madrid, Spain.
↵?To whom correspondence should be sent. E-mail: aef24@cam.ac.uk (A.E.F.); taubenbergerj@niaid.nih.gov (J.K.T.); paul.digard@roslin.ed.ac.uk (P.D.)
Abstract
Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame (?X-ORF?), accessed via ribosomal frameshifting. The FS product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T-lymphocyte signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.
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