title: Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus.
abstract: A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus.
  
  
  OBJECTIVE
  Identification of a novel coronavirus causing fatal respiratory infection in humans raises concerns about a possible widespread outbreak of severe respiratory infection similar to the one caused by SARS-CoV. Using a human lung epithelial cell line and global transcriptomic profiling, we identified differences in the host response between HCoV-EMC and SARS-CoV. This enables rapid assessment of viral properties and the ability to anticipate possible differences in human clinical responses to HCoV-EMC and SARS-CoV. We used this information to predict potential effective drugs against HCoV-EMC, a method that could be more generally used to identify candidate therapeutics in future disease outbreaks. These data will help to generate hypotheses and make rapid advancements in characterizing this new virus.
authors: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
authors: Laurence
authors: L
authors: Josset
authors: Vineet D
authors: VD
authors: Menachery
authors: Lisa E
authors: LE
authors: Gralinski
authors: Sudhakar
authors: S
authors: Agnihothram
authors: Pavel
authors: P
authors: Sova
authors: Victoria S
authors: VS
authors: Carter
authors: Boyd L
authors: BL
authors: Yount
authors: Rachel L
authors: RL
authors: Graham
authors: Ralph S
authors: RS
authors: Baric
authors: Michael G
authors: MG
authors: Katze
mesh_terms: D002460:Cell Line; D017934:Coronavirus / Q000302:isolation & purification / Q000472:pathogenicity* / Q000502:physiology; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance; D045169:Severe Acute Respiratory Syndrome / Q000821:virology*; D059467:Transcriptome; D014779:Virus Replication
references: Immunology. 1997 Jul;91(3):458-63
references: 9301537
references: J Immunol. 2011 Nov 15;187(10):5357-62
references: 21964025
references: PLoS One. 2010 Jan 15;5(1):e8729
references: 20090954
references: N Engl J Med. 2012 Nov 8;367(19):1814-20
references: 23075143
references: J Virol. 2001 Jul;75(13):6022-32
references: 11390604
references: N Engl J Med. 2003 May 15;348(20):1967-76
references: 12690091
references: Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii83-8
references: 17038480
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12995-3000
references: 14569023
references: BMC Genomics. 2009 Jan 14;10:22
references: 19144180
references: PLoS One. 2010 Oct 04;5(10):
references: 20957181
references: Arch Med Res. 2013 Feb;44(2):93-8
references: 23376055
references: PLoS Pathog. 2011 Oct;7(10):e1002331
references: 22046132
references: mBio. 2013 Jan 15;4(1):
references: 23322635
references: Protein Cell. 2013 Apr;4(4):248-50
references: 23549610
references: Microbiol Mol Biol Rev. 2012 Mar;76(1):33-45
references: 22390971
references: Methods Mol Biol. 2000;132:365-86
references: 10547847
references: J Virol. 2009 Jul;83(13):6883-99
references: 19386722
references: Nat Rev Clin Oncol. 2013 Mar;10(3):143-53
references: 23400000
references: Eur J Pharmacol. 2010 Jun 10;635(1-3):212-8
references: 20226180
references: Biol Chem. 2011 Oct;392(10):837-47
references: 21823902
references: Eur J Pharmacol. 2013 Jan 5;698(1-3):455-62
references: 23183108
references: Nat Rev Immunol. 2009 Jul;9(7):503-13
references: 19498380
references: J Virol. 2011 Nov;85(21):10955-67
references: 21865398
references: Nat Rev Cancer. 2007 Jan;7(1):54-60
references: 17186018
references: J Med Chem. 2011 Nov 24;54(22):7797-814
references: 21888439
references: PLoS Med. 2006 Sep;3(9):e343
references: 16968120
references: J Immunol. 2009 Oct 15;183(8):5301-10
references: 19783685
references: Immunology. 2003 Oct;110(2):163-9
references: 14511229
references: mBio. 2013 Feb 19;4(1):e00611-12
references: 23422412
references: Virus Res. 2012 Apr;165(1):112-7
references: 22349148
references: Cell Microbiol. 2013 Jul;15(7):1198-211
references: 23320394
references: Nature. 2013 Mar 14;495(7440):251-4
references: 23486063
references: mBio. 2012 Nov 20;3(6):
references: 23170002
references: mBio. 2012 Dec 11;3(6):
references: 23232719
references: Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32
references: 22390970
references: Euro Surveill. 2012 Oct 04;17(40):20290
references: 23078800
references: J Virol. 2003 May;77(10):5649-56
references: 12719557
references: J Gen Virol. 2005 Feb;86(Pt 2):375-384
references: 15659757
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: J Virol Methods. 2011 Jun;174(1-2):144-9
references: 21458491
references: Sci Transl Med. 2011 Aug 17;3(96):96ra77
references: 21849665
references: J Virol. 2013 Apr;87(7):3885-902
references: 23365422
references: N Engl J Med. 2003 Dec 18;349(25):2431-41
references: 14681510
references: Trends Immunol. 2012 Jul;33(7):343-9
references: 22476048
references: Expert Opin Biol Ther. 2009 Nov;9(11):1369-82
references: 19732026
references: J Exp Med. 1998 Jan 5;187(1):97-104
references: 9419215
references: J Biol Chem. 1996 Nov 29;271(48):30864-9
references: 8940070
references: J Gen Virol. 2007 Mar;88(Pt 3):942-950
references: 17325368
references: Trends Immunol. 2003 May;24(5):278-85
references: 12738423