The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus.
BACKGROUND
The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ anti-immune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation.


RESULTS
We validated our predictions in 18 different knockout (KO) mouse strains, showing that network topology provides significant predictive power to identify genes that are important for viral infection. We identified a novel player in the immune response to virus infection, Kepi, an inhibitory subunit of the protein phosphatase 1 (PP1) complex, which protects against SARS-CoV pathogenesis. We also found that receptors for the proinflammatory cytokine tumor necrosis factor alpha (TNFα) promote pathogenesis, presumably through excessive inflammation.


CONCLUSIONS
The current study provides validation of network modeling approaches for identifying important players in virus infection pathogenesis, and a step forward in understanding the host response to an important infectious disease. The results presented here suggest the role of Kepi in the host response to SARS-CoV, as well as inflammatory activity driving pathogenesis through TNFα signaling in SARS-CoV infections. Though we have reported the utility of this approach in bacterial and cell culture studies previously, this is the first comprehensive study to confirm that network topology can be used to predict phenotypes in mice with experimental validation.
Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
Jason E
JE
McDermott
Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA, 99354, USA. Hugh.Mitchell@pnnl.gov.
Hugh D
HD
Mitchell
Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA.
Lisa E
LE
Gralinski
Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Amie J
AJ
Eisfeld
Department of Microbiology, University of Washington, Seattle, WA, 98195, USA.
Laurence
L
Josset
Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
Armand
A
Bankhead
Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Gabriele
G
Neumann
Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
Susan C
SC
Tilton
Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA.
Alexandra
A
Schäfer
Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Chengjun
C
Li
Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, 53715, USA.
Shufang
S
Fan
Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
Shannon
S
McWeeney
Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Ralph S
RS
Baric
Department of Microbiology, University of Washington, Seattle, WA, 98195, USA.
Michael G
MG
Katze
Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA, 99354, USA.
Katrina M
KM
Waters
Network; Pathogenicity; SARS coronavirus; Systems biology
Mol Cell. 2009 Mar 13;33(5):537-45
19285938
BMC Genomics. 2009 Aug 27;10:405
19712483
J Virol. 2014 Jan;88(2):913-24
24198408
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14040-5
16169905
BMC Syst Biol. 2012 Apr 30;6:28
22546282
PLoS Pathog. 2008 Dec;4(12):e1000240
19079579
N Engl J Med. 2012 Nov 8;367 (19):1814-20
23075143
Nat Immunol. 2008 May;9(5):533-41
18362886
BMC Syst Biol. 2011 Jun 28;5:100
21711513
N Engl J Med. 2003 May 15;348(20):1995-2005
12671061
Genome Res. 2008 Feb;18(2):206-13
18083776
J Virol. 2011 Nov;85(22):11646-54
21917952
BMC Genomics. 2013 Jan 22;14:46
23339624
PLoS One. 2014 Aug 29;9(8):e106132
25170616
J Cell Physiol. 2007 Aug;212(2):450-62
17311286
PLoS Comput Biol. 2012;8(2):e1002375
22383865
Biomed Rep. 2013 Nov;1(6):918-924
24649053
Free Radic Biol Med. 2009 May 15;46(10):1428-36
19269318
Mol Biosyst. 2011 Aug;7(8):2407-18
21698331
J Comput Biol. 2009 Feb;16(2):169-80
19178137
MBio. 2013 Aug 06;4(4):null
23919993
PLoS One. 2012;7(6):e36465
22745654
PLoS Biol. 2007 Jan;5(1):e8
17214507
MBio. 2014 May 20;5(3):e01174-14
24846384
Pac Symp Biocomput. 2011;:314-25
21121059
Arch Virol. 2010 Aug;155(8):1273-9
20532927
J Virol. 2011 Nov;85(21):10955-67
21865398
PLoS One. 2011 Feb 14;6(2):e14673
21339814
MBio. 2013 Apr 30;4(3):e00165-13
23631916
J Pathol. 2006 Nov;210(3):288-97
17031779
Cell. 2013 Jul 3;154(1):197-212
23827683
J Biol Chem. 2004 Oct 22;279(43):44695-703
15292176
Diabetologia. 2012 Aug;55(8):2205-13
22584726
J Virol. 2013 Jul;87(14):7790-2
23678167
Drug Discov Today. 2005 Jun 15;10(12):857-64
15970268
Phys Rev E Stat Nonlin Soft Matter Phys. 2001 Jul;64(1 Pt 2):016132
11461356
Nat Rev Immunol. 2012 Oct;12(10):687-95
22976433
Dis Markers. 2010;28(4):253-66
20534910
J Virol. 2010 Feb;84(3):1289-301
19906920
PLoS Pathog. 2007 Jan;3(1):e5
17222058
Arch Biochem Biophys. 2003 Sep 1;417(1):44-52
12921778
J Biol Chem. 2009 Dec 18;284(51):35273-7
19846560
BMC Bioinformatics. 2006 Sep 06;7 Suppl 2:S13
17118134
PLoS Pathog. 2010 Apr 08;6(4):e1000849
20386712
Am J Respir Crit Care Med. 2013 Jan 1;187(1):65-77
23144331
Biostatistics. 2003 Apr;4(2):249-64
12925520