title: Characterization of Glycoprotein-Mediated Entry of Severe Fever with Thrombocytopenia Syndrome Virus.
abstract: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high case fatality rate caused by SFTS virus (SFTSV). Effective vaccines and specific therapies for SFTS are urgently sought, and investigation into virus-host cell interactions is expected to contribute to the development of antiviral strategies. In this study, we have developed a pseudotype vesicular stomatitis virus (VSV) bearing the unmodified Gn/Gc glycoproteins (GPs) of SFTSV (SFTSVpv). We have analyzed the host cell entry of this pseudotype virus and native SFTSV. Both SFTSVpv and SFTSV exhibited high infectivity in various mammalian cell lines. The use of lysosomotropic agents indicated that virus entry occurred via pH-dependent endocytosis. SFTSVpv and SFTSV infectivity was neutralized by serial dilutions of convalescent-phase patient sera. Entry of SFTSVpv and growth of SFTSV were increased in Raji cells expressing not only the C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) but also DC-SIGN-related (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin). 25-Hydroxycholesterol (25HC), a soluble oxysterol metabolite, inhibited the cell entry of SFTSVpv and the membrane fusion of SFTSV. These results indicate that pH-dependent endocytosis of SFTSVpv and SFTSV is enhanced by attachment to certain C-type lectins. SFTSVpv is an appropriate model for the investigation of SFTSV-GP-mediated cell entry and virus neutralization at lower biosafety levels. Furthermore, 25HC may represent a potential antiviral agent against SFTS.
  
  
  
  SFTSV is a recently discovered bunyavirus associated with SFTS, a viral hemorrhagic fever with a high case fatality rate endemic to China, South Korea, and Japan. Because little is known about the characteristics of the envelope protein and entry mechanisms of SFTSV, further studies will be required for the development of a vaccine or effective therapies. In this study, we investigated the mechanism of SFTSV cell entry using SFTSVpv and the native virus. SFTSV can grow in nonsusceptible cell lines in the presence of certain C-type lectins. Moreover, 25HC, an oxysterol metabolite, may represent a potential therapeutic inhibitor of SFTSV infection.
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tani
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimojima
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Shuetsu
authors.initials: S
authors.lastname: Fukushi
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Fukuma
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Taniguchi
authors.affiliation: Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morikawa
authors.affiliation: Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan msaijo@niid.go.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saijo
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002681:China; D004705:Endocytosis; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006888:Hydroxycholesterols / Q000494:pharmacology; D037181:Lectins, C-Type / Q000378:metabolism; D009500:Neutralization Tests; D010217:Phlebotomus Fever / Q000821:virology; D016856:Phlebovirus / Q000737:chemistry / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013921:Thrombocytopenia / Q000821:virology*; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053586:Virus Internalization; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D006888:Hydroxycholesterols; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D014759:Viral Envelope Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human; C007997:25-hydroxycholesterol