title: The relationship between the structure of the tick-borne encephalitis virus strains and their pathogenic properties.
abstract: Tick-borne encephalitis virus (TBEV) is transmitted to vertebrates by taiga or forest ticks through bites, inducing disease of variable severity. The reasons underlying these differences in the severity of the disease are unknown. In order to identify genetic factors affecting the pathogenicity of virus strains, we have sequenced and compared the complete genomes of 34 Far-Eastern subtype (FE) TBEV strains isolated from patients with different disease severity (Primorye, the Russian Far East). We analyzed the complete genomes of 11 human pathogenic strains isolated from the brains of dead patients with the encephalitic form of the disease (Efd), 4 strains from the blood of patients with the febrile form of TBE (Ffd), and 19 strains from patients with the subclinical form of TBE (Sfd). On the phylogenetic tree, pathogenic Efd strains formed two clusters containing the prototype strains, Senzhang and Sofjin, respectively. Sfd strains formed a third separate cluster, including the Oshima strain. The strains that caused the febrile form of the disease did not form a separate cluster. In the viral proteins, we found 198 positions with at least one amino acid residue substitution, of which only 17 amino acid residue substitutions were correlated with the variable pathogenicity of these strains in humans and they authentically differed between the groups. We considered the role of each amino acid substitution and assumed that the deletion of 111 amino acids in the capsid protein in combination with the amino acid substitutions R16K and S45F in the NS3 protease may affect the budding process of viral particles. These changes may be the major reason for the diminished pathogenicity of TBEV strains. We recommend Sfd strains for testing as attenuation vaccine candidates.
authors.affiliation: Limnological Institute, Siberian Branch, Russian Academy of Sciences, Irkutsk, Russia.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Belikov
authors.affiliation: Limnological Institute, Siberian Branch, Russian Academy of Sciences, Irkutsk, Russia.
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Kondratov
authors.affiliation: Limnological Institute, Siberian Branch, Russian Academy of Sciences, Irkutsk, Russia.
authors.forename: Ulyana V
authors.initials: UV
authors.lastname: Potapova
authors.affiliation: Research Institute of Epidemiology and Microbiology, Siberian Branch, Russian Academy of Medical Sciences, Vladivostok, Russia.
authors.forename: Galina N
authors.initials: GN
authors.lastname: Leonova
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics; D002681:China; D004669:Encephalitis Viruses, Tick-Borne / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D004675:Encephalitis, Tick-Borne / Q000097:blood / Q000821:virology*; D040342:Genetic Structures; D016679:Genome, Viral / Q000235:genetics*; D005843:Geography; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000737:chemistry / Q000235:genetics; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D012426:Russia; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D014774:Virulence / Q000235:genetics; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D036022:Capsid Proteins; D020365:RNA Helicases; D012367:RNA, Viral; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
references.citation: Vopr Virusol. 2005 May-Jun;50(3):26-32
references.pmid: 16078431
references.citation: J Virol. 2003 Oct;77(20):11296-8
references.pmid: 14512579
references.citation: Acta Virol. 1997 Dec;41(6):325-8
references.pmid: 9607090
references.citation: Antiviral Res. 2003 Jan;57(1-2):129-46
references.pmid: 12615309
references.citation: J Virol. 2005 Oct;79(20):12828-39
references.pmid: 16188985
references.citation: J Virol. 2002 May;76(10):4773-84
references.pmid: 11967294
references.citation: J Gen Virol. 2004 Apr;85(Pt 4):1007-1018
references.pmid: 15039543
references.citation: J Biol Chem. 2007 Mar 23;282(12):8873-82
references.pmid: 17276984
references.citation: J Mol Evol. 1980 Dec;16(2):111-20
references.pmid: 7463489
references.citation: J Virol. 2000 Oct;74(20):9601-9
references.pmid: 11000232
references.citation: J Virol. 1998 Mar;72(3):2132-40
references.pmid: 9499069
references.citation: J Virol. 2001 Jun;75(12):5627-37
references.pmid: 11356970
references.citation: Vopr Virusol. 2007 Sep-Oct;52(5):8-10
references.pmid: 18041217
references.citation: Clin Microbiol Infect. 2004 Dec;10(12):1040-55
references.pmid: 15606630
references.citation: Vaccine. 2003 Sep 8;21(25-26):4043-51
references.pmid: 12922141
references.citation: J Virol. 2006 Feb;80(3):1427-39
references.pmid: 16415020
references.citation: RNA. 1997 Jul;3(7):779-91
references.pmid: 9214660
references.citation: J Virol. 2005 Jun;79(11):6631-43
references.pmid: 15890901
references.citation: Mol Biol Evol. 2002 Dec;19(12):2333-6
references.pmid: 12446826
references.citation: J Virol. 1996 Jul;70(7):4549-57
references.pmid: 8676481
references.citation: Virology. 1989 Aug;171(2):637-9
references.pmid: 2548336
references.citation: J Mol Biol. 2009 Feb 6;385(5):1568-77
references.pmid: 19059417
references.citation: Antiviral Res. 2013 May;98(2):192-208
references.pmid: 23523765
references.citation: BMC Evol Biol. 2004 Jun 28;4:18
references.pmid: 15222900
references.citation: Virology. 1987 Apr;157(2):330-7
references.pmid: 3029975
references.citation: Virus Res. 2005 Aug;111(2):161-74
references.pmid: 15871909
references.citation: J Biomol Struct Dyn. 2012;30(6):638-51
references.pmid: 22730949
references.citation: Nat Methods. 2011 Sep 29;8(10):785-6
references.pmid: 21959131
references.citation: J Infect Dis. 2006 Apr 15;193(8):1078-88
references.pmid: 16544248
references.citation: Proc Int Conf Intell Syst Mol Biol. 1998;6:175-82
references.pmid: 9783223
references.citation: J Virol. 1999 Apr;73(4):3108-16
references.pmid: 10074162
references.citation: Vopr Virusol. 2001 Jan-Feb;46(1):12-6
references.pmid: 11233280
references.citation: J Virol. 2006 Mar;80(5):2396-404
references.pmid: 16474146
references.citation: Mol Biol Evol. 2007 Aug;24(8):1586-91
references.pmid: 17483113
references.citation: J Virol. 1998 Mar;72(3):2141-9
references.pmid: 9499070
references.citation: Vopr Virusol. 2001 Jan-Feb;46(1):17-22
references.pmid: 11233281
references.citation: Virology. 2010 May 25;401(1):80-9
references.pmid: 20207389
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W609-12
references.pmid: 16845082
references.citation: PLoS One. 2013 Apr 09;8(4):e61094
references.pmid: 23585873
references.citation: Genetika. 2010 Mar;46(3):356-63
references.pmid: 20391780
references.citation: J Gen Virol. 2001 Jun;82(Pt 6):1319-1328
references.pmid: 11369875
references.citation: J Virol. 2007 May;81(9):4753-65
references.pmid: 17301146
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3406-15
references.pmid: 12824337
references.citation: Adv Virus Res. 2003;60:233-72
references.pmid: 14689696
references.citation: Virology. 2007 Sep 15;366(1):8-15
references.pmid: 17658577
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14333-8
references.pmid: 14612562
references.citation: J Virol. 2011 Nov;85(21):11274-82
references.pmid: 21880777
references.citation: J Virol. 2014 May;88(10):5406-20
references.pmid: 24574402
references.citation: Virology. 1998 Jun 5;245(2):203-15
references.pmid: 9636360
references.citation: J Virol. 2003 Jul;77(14):7804-13
references.pmid: 12829820
references.citation: Ticks Tick Borne Dis. 2011 Dec;2(4):179-82
references.pmid: 22108009
references.citation: Genes Dev. 2006 Aug 15;20(16):2238-49
references.pmid: 16882970
references.citation: J Virol. 2005 Jul;79(13):8004-13
references.pmid: 15956546
references.citation: Virology. 2008 May 25;375(1):223-35
references.pmid: 18289628
references.citation: J Virol. 1991 May;65(5):2467-75
references.pmid: 2016768
references.citation: J Virol. 2005 Nov;79(22):13924-33
references.pmid: 16254328
references.citation: Virology. 1995 Oct 20;213(1):169-78
references.pmid: 7483260
references.citation: Virus Res. 2012 Aug;167(2):310-3
references.pmid: 22659297
references.citation: Mol Cell. 2001 Mar;7(3):593-602
references.pmid: 11463384
references.citation: J Virol. 2013 Feb;87(4):2367-72
references.pmid: 23236063
references.citation: Vopr Virusol. 2007 Nov-Dec;52(6):13-7
references.pmid: 18050711
references.citation: J Virol. 2003 Sep;77(18):10004-14
references.pmid: 12941911
references.citation: J Virol. 1994 Jun;68(6):3794-802
references.pmid: 8189517
references.citation: Virology. 1990 Jan;174(1):250-63
references.pmid: 2136778
references.citation: J Biol Stand. 1987 Oct;15(4):305-13
references.pmid: 3680299
references.citation: EMBO J. 2002 Jun 3;21(11):2757-68
references.pmid: 12032088
references.citation: J Mol Microbiol Biotechnol. 2011;21(1-2):71-81
references.pmid: 22248544
references.citation: J Mol Biol. 2001 Jan 19;305(3):567-80
references.pmid: 11152613
references.citation: Proteins. 2003;53 Suppl 6:430-5
references.pmid: 14579332
references.citation: J Virol. 2001 Jul;75(14):6719-28
references.pmid: 11413342
references.citation: Curr Opin Chem Biol. 2001 Feb;5(1):51-6
references.pmid: 11166648
references.citation: Virology. 1989 Jul;171(1):302-5
references.pmid: 2525840
references.citation: Travel Med Infect Dis. 2003 Aug;1(3):181-4
references.pmid: 17291912
references.citation: Virology. 1996 Feb 15;216(2):317-25
references.pmid: 8607261
references.citation: Virology. 2013 Aug 15;443(1):89-98
references.pmid: 23735441
references.citation: J Virol. 1999 Jun;73(6):4611-21
references.pmid: 10233920
references.citation: Euro Surveill. 2008 Jun 26;13(26):
references.pmid: 18761916
references.citation: Virology. 2004 Oct 25;328(2):208-18
references.pmid: 15464841
references.citation: J Virol. 2002 Apr;76(7):3534-43
references.pmid: 11884577
references.citation: Virology. 1988 Jan;162(1):187-96
references.pmid: 2827377
references.citation: J Immunol. 2005 Jan 1;174(1):395-403
references.pmid: 15611263
references.citation: J Gen Virol. 2006 Sep;87(Pt 9):2605-2614
references.pmid: 16894199
references.citation: J Infect Dis. 2009 Oct 15;200(8):1261-70
references.pmid: 19754307
references.citation: Viruses. 2010 Feb;2(2):676-691
references.pmid: 21994652
references.citation: Arch Virol. 2007;152(5):1027-34
references.pmid: 17277902
references.citation: J Mol Biol. 1987 Nov 5;198(1):33-41
references.pmid: 2828633
references.citation: J Virol. 1993 Apr;67(4):2034-42
references.pmid: 8383225
references.citation: J Virol. 2003 Feb;77(3):2265-70
references.pmid: 12525663
references.citation: J Comput Chem. 2003 Dec;24(16):1999-2012
references.pmid: 14531054
references.citation: Immunol Res. 2009;43(1-3):172-86
references.pmid: 18841330
references.citation: Microb Pathog. 1992 Nov;13(5):399-409
references.pmid: 1297916
references.citation: Virology. 2001 Apr 10;282(2):288-300
references.pmid: 11289811
references.citation: J Virol. 1999 Jul;73(7):6104-10
references.pmid: 10364366
references.citation: J Virol. 2007 Jul;81(13):6936-46
references.pmid: 17459929
references.citation: Structure. 2004 Jul;12(7):1157-63
references.pmid: 15242592
references.citation: J Virol. 2010 Apr;84(7):3503-15
references.pmid: 20106931
references.citation: J Virol. 1994 Sep;68(9):5765-71
references.pmid: 8057458