The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways.
The "Spanish influenza" of 1918 claimed an unprecedented number of lives, yet the determinants of virulence for this virus are still not fully understood. Here, we used functional genomics and an in vitro human lung epithelial cell infection model to define the global host transcriptional response to the eight-gene 1918 virus. To better understand the role of the 1918 virus NS1 gene, we also evaluated the host response to a reassortant 1918 virus containing the NS1 gene from A/Texas/36/91 (a seasonal isolate of human influenza virus), as well as the host response to a reassortant of A/Texas/36/91 containing the 1918 NS1 gene. Genomic analyses revealed that the 1918 virus blocked the transcription of multiple interferon-stimulated genes and also downregulated a network of genes associated with lipid metabolism. In contrast, the expression of genes encoding chemokines and cytokines, which serve to attract infiltrating immune cells, was upregulated. Viruses containing the NS1 gene from A/Texas/36/91 induced a significant increase in type I interferon signaling but did not repress lipid metabolism. The 1918 NS1 gene may therefore have contributed to the virulence of the 1918 pandemic virus by disrupting the innate immune response, inducing hypercytokinemia, and by blocking the transcription of certain lipid-based proinflammatory mediators that function as part of the host antiviral response.
Billharz
Rosalind
R
Department of Microbiology and Washington National Primate Research Center, University of Washington, Seattle, WA 98195-8070, USA.
Zeng
Hui
H
Proll
Sean C
SC
Korth
Marcus J
MJ
Lederer
Sharon
S
Albrecht
Randy
R
Goodman
Alan G
AG
Rosenzweig
Elizabeth
E
Tumpey
Terrence M
TM
García-Sastre
Adolfo
A
Katze
Michael G
MG
D002460:Cell Line; D004196:Disease Outbreaks; D004847:Epithelial Cells / Q000166:cytology / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D007372:Interferons / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008168:Lung / Q000166:cytology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D010948:Viral Plaque Assay
C085820:INS1 protein, influenza virus; D011506:Proteins; D011993:Recombinant Fusion Proteins; D017361:Viral Nonstructural Proteins; D007372:Interferons
J Virol. 2007 Jan;81(2):514-24
17079289
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4543-7
8506296
J Gen Virol. 1992 Dec;73 ( Pt 12):3325-9
1469370
Mol Cell Biol. 2000 Sep;20(17):6259-68
10938102
Am J Respir Cell Mol Biol. 2007 Mar;36(3):263-9
17053203
J Virol. 2007 Dec;81(23):12730-9
17881440
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2746-51
11226311
Virol J. 2006 Nov 22;3:98
17121680
Nature. 2004 Oct 7;431(7009):703-7
15470432
Mol Cell. 1998 Jun;1(7):991-1000
9651582
J Virol. 2005 Aug;79(15):10053-8
16014965
J Virol. 2007 Apr;81(7):3058-67
17229704
J Virol. 2009 Feb;83(4):1611-6
19052083
Virology. 2007 Jun 20;363(1):236-43
17320139
J Virol. 2004 Sep;78(17):9499-511
15308742
Virology. 2006 May 25;349(1):13-21
16466763
Nature. 2005 Oct 6;437(7060):889-93
16208372
PLoS Pathog. 2007 Oct 5;3(10):1414-21
17922571
J Virol. 2005 Jun;79(12):7535-43
15919908
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4381-6
18334632
Biochemistry. 2004 Feb 24;43(7):1950-62
14967035
J Virol. 2000 Jul;74(13):6203-6
10846107
Nat Struct Biol. 1997 Nov;4(11):891-5
9360601
J Virol. 2007 Jul;81(13):7011-21
17442719
Virus Res. 2004 Jul;103(1-2):107-13
15163498
Cytogenet Genome Res. 2004;105(1):11-7
15218252
Virology. 2003 Mar 15;307(2):386-95
12667806
Apoptosis. 2007 Aug;12(8):1419-32
17468837
J Interferon Cytokine Res. 1998 Sep;18(9):757-66
9781815
EMBO J. 1999 Apr 15;18(8):2273-83
10205180
J Virol. 2000 Dec;74(24):11566-73
11090154
J Virol. 2006 Nov;80(21):10813-28
16928763
Cell Host Microbe. 2009 May 8;5(5):439-49
19454348
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7100-5
16627618
Virology. 1998 Dec 20;252(2):324-30
9878611
J Virol. 2002 Feb;76(3):1206-12
11773396
Biochemistry. 1990 Dec 25;29(51):11280-92
2271712
Methods Mol Biol. 2005;304:455-9
16061997
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3064-9
18287069
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6924-9
9618515
J Gen Virol. 2007 Jan;88(Pt 1):13-18
17170431
Nature. 2007 Jan 18;445(7125):319-23
17230189
Science. 2006 Mar 17;311(5767):1576-80
16439620
Methods. 2001 Dec;25(4):402-8
11846609
Nat Genet. 2001 Dec;29(4):365-71
11726920
J Virol. 2005 Dec;79(23):14933-44
16282492
J Biol Chem. 2008 Aug 22;283(34):23397-409
18534979
Cell Microbiol. 2007 Apr;9(4):930-8
17140406
Nature. 2006 Oct 5;443(7111):578-81
17006449
J Virol. 2007 Jun;81(11):5995-6006
17376915
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3166-71
14963236
Science. 2005 Oct 7;310(5745):77-80
16210530
J Virol. 1999 Mar;73(3):2425-33
9971827
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10736-41
12149435