title: Severe fever with thrombocytopenia virus glycoproteins are targeted by neutralizing antibodies and can use DC-SIGN as a receptor for pH-dependent entry into human and animal cell lines.
abstract: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel bunyavirus that recently emerged in China. Infection with SFTSV is associated with case-fatality rates of up to 30%, and neither antivirals nor vaccines are available at present. Development of antiviral strategies requires the elucidation of virus-host cell interactions. Here, we analyzed host cell entry of SFTSV. Employing lentiviral and rhabdoviral vectors, we found that the Gn/Gc glycoproteins (Gn/Gc) of SFTSV mediate entry into a broad range of human and animal cell lines, as well as human macrophages and dendritic cells. The Gn/Gc proteins of La Crosse virus (LACV) and Rift Valley Fever Virus (RVFV), other members of the bunyavirus family, facilitated entry into an overlapping but not identical range of cell lines, suggesting that SFTSV, LACV, and RVFV might differ in their receptor requirements. Entry driven by SFTSV Gn/Gc was dependent on low pH but did not require the activity of the pH-dependent endosomal/lysosomal cysteine proteases cathepsins B and L. Instead, the activity of a cellular serine protease was required for infection driven by SFTSV and LACV Gn/Gc. Sera from convalescent SFTS patients inhibited SFTSV Gn/Gc-driven host cell entry in a dose-dependent fashion, demonstrating that the vector system employed is suitable to detect neutralizing antibodies. Finally, the C-type lectin DC-SIGN was found to serve as a receptor for SFTSV Gn/Gc-driven entry into cell lines and dendritic cells. Our results provide initial insights into cell tropism, receptor usage, and proteolytic activation of SFTSV and will aid in the understanding of viral spread and pathogenesis.
authors: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors: Heike
authors: H
authors: Hofmann
authors: Xingxing
authors: X
authors: Li
authors: Xiaoai
authors: X
authors: Zhang
authors: Wei
authors: W
authors: Liu
authors: Annika
authors: A
authors: Kühl
authors: Franziska
authors: F
authors: Kaup
authors: Samantha S
authors: SS
authors: Soldan
authors: Francisco
authors: F
authors: González-Scarano
authors: Friedemann
authors: F
authors: Weber
authors: Yuxian
authors: Y
authors: He
authors: Stefan
authors: S
authors: Pöhlmann
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D016851:Orthobunyavirus / Q000276:immunology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism*; D056189:Viral Tropism; D053586:Virus Internalization; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D057057:Serine Proteases; D014759:Viral Envelope Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
references: J Virol. 2011 Sep;85(17):9227-34
references: 21715500
references: Cell. 2000 Mar 3;100(5):587-97
references: 10721995
references: Cell Host Microbe. 2011 Jul 21;10(1):75-88
references: 21767814
references: Virology. 2003 Jan 5;305(1):115-23
references: 12504546
references: Virology. 1993 Aug;195(2):511-20
references: 8337827
references: J Gen Virol. 2011 Nov;92(Pt 11):2467-2484
references: 21865443
references: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7074-9
references: 9618541
references: PLoS One. 2011;6(10):e25858
references: 21998709
references: J Virol. 2011 Jul;85(13):6098-105
references: 21450816
references: Tijdschr Diergeneeskd. 2012 Feb;137(2):106-11
references: 22393844
references: Dev Cell. 2006 Jun;10(6):839-50
references: 16740485
references: J Gen Virol. 1994 Dec;75 ( Pt 12):3441-51
references: 7996137
references: N Engl J Med. 2011 Apr 21;364(16):1523-32
references: 21410387
references: Clin Infect Dis. 2011 Dec;53(12):1208-14
references: 22028437
references: Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):10053-8
references: 22665769
references: Virology. 2007 Feb 20;358(2):273-82
references: 17027056
references: J Cell Biol. 1980 Feb;84(2):404-20
references: 6991511
references: PLoS Negl Trop Dis. 2012;6(12):e1923
references: 23236527
references: Emerg Infect Dis. 2012 Jun;18(6):1005-6
references: 22607989
references: Clin Infect Dis. 2012 Jan 15;54(2):249-52
references: 22095565
references: Gene. 1991 Dec 15;108(2):193-9
references: 1660837
references: J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):535-43
references: 18209676
references: J Virol. 2002 Feb;76(4):1866-75
references: 11799181
references: J Virol. 1999 May;73(5):3951-9
references: 10196290
references: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14764-9
references: 9405687
references: Virology. 2012 Mar 1;424(1):3-10
references: 22222211
references: Cell Host Microbe. 2010 Jun 25;7(6):488-99
references: 20542252
references: Emerg Infect Dis. 2012 Aug;18(8):1333-5
references: 22840657
references: AIDS Res Hum Retroviruses. 2003 Sep;19(9):817-23
references: 14585212
references: J Virol. 2003 Jan;77(2):1368-81
references: 12502853
references: J Gen Virol. 2008 Sep;89(Pt 9):2157-2166
references: 18753225
references: Virology. 1995 Feb 1;206(2):935-44
references: 7531918
references: J Virol. 2004 Jun;78(12):6134-42
references: 15163706
references: Virology. 2011 Oct 25;419(2):72-83
references: 21907381
references: Proc Natl Acad Sci U S A. 1998 May 12;95(10):5762-7
references: 9576958
references: Tijdschr Diergeneeskd. 2012 Feb;137(2):112-5
references: 22393845
references: PLoS One. 2012;7(4):e35587
references: 22545121
references: Virology. 2005 Sep 30;340(2):224-36
references: 16051304
references: J Gen Virol. 2005 May;86(Pt 5):1455-1465
references: 15831958
references: Cell Microbiol. 2010 Nov;12(11):1553-61
references: 20854332
references: J Virol. 2011 Jan;85(1):334-47
references: 21047970
references: Clin Diagn Lab Immunol. 2003 Jan;10(1):154-60
references: 12522053
references: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11876-81
references: 16081529
references: J Gen Virol. 1990 Apr;71 ( Pt 4):767-73
references: 2157795
references: EMBO J. 1988 Feb;7(2):513-8
references: 3259178
references: Clin Microbiol Rev. 2010 Apr;23(2):412-41
references: 20375360
references: J Virol. 2006 Apr;80(8):4174-8
references: 16571833
references: Science. 2005 Jun 10;308(5728):1643-5
references: 15831716
references: Virology. 2004 Jan 5;318(1):17-23
references: 14972530
references: J Gen Virol. 1987 Feb;68 ( Pt 2):387-99
references: 3029282
references: Vaccine. 2009 Nov 5;27 Suppl 4:D69-72
references: 19837291
references: N Engl J Med. 2012 Aug 30;367(9):834-41
references: 22931317
references: Virus Res. 2008 Dec;138(1-2):139-43
references: 18840482
references: J Virol. 1998 Apr;72(4):3155-60
references: 9525641
references: Vector Borne Zoonotic Dis. 2012 Feb;12(2):156-60
references: 21955213
references: J Infect Dis. 2011 Nov;204 Suppl 3:S840-9
references: 21987760
references: J Cell Biol. 1996 Dec;135(5):1249-60
references: 8947549
references: J Virol. 2012 Aug;86(15):7988-8001
references: 22623766
references: J Virol. 2000 Nov;74(21):10074-80
references: 11024136
references: J Infect Dis. 2011 Nov;204 Suppl 3:S957-67
references: 21987776
references: J Virol. 2008 May;82(9):4257-64
references: 18305044
references: J Neuroimmune Pharmacol. 2010 Sep;5(3):428-42
references: 20652430
references: Virology. 1988 Sep;166(1):275-80
references: 3046119
references: Cell. 2000 Nov 10;103(4):679-89
references: 11106737