Giuseppe
Emeritus
[Source: Journal of Virology, full text: (LINK). Abstract, edited.]
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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
Heike Hofmann<SUP>a</SUP>, Xingxing Li<SUP>b</SUP>, Xiaoai Zhang<SUP>c</SUP>, Wei Liu<SUP>c</SUP>, Annika K?hl<SUP>a</SUP>, Franziska Kaup<SUP>a</SUP>, Samantha S. Soldan<SUP>d</SUP>, Francisco Gonz?lez-Scarano<SUP>e</SUP>, Friedemann Weber<SUP>f</SUP>, Yuxian He<SUP>b</SUP> and Stefan P?hlmann<SUP>a</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Infection Biology Unit, German Primate Center, G?ttingen, Germany <SUP>b</SUP>Institute of Pathogen Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China <SUP>c</SUP>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China <SUP>d</SUP>Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA <SUP>e</SUP>Department of Neurology, University of Texas School of Medicine at San Antonio, San Antonio, Texas, USA <SUP>f</SUP>Institute for Virology, Philipps University Marburg, Marburg, Germany
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.
FOOTNOTES
Received 3 October 2012. Accepted 24 January 2013.
Address correspondence to Stefan P?hlmann, s.poehlmann@dpz.eu.
Published ahead of print 6 February 2013
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-Heike Hofmann<SUP>a</SUP>, Xingxing Li<SUP>b</SUP>, Xiaoai Zhang<SUP>c</SUP>, Wei Liu<SUP>c</SUP>, Annika K?hl<SUP>a</SUP>, Franziska Kaup<SUP>a</SUP>, Samantha S. Soldan<SUP>d</SUP>, Francisco Gonz?lez-Scarano<SUP>e</SUP>, Friedemann Weber<SUP>f</SUP>, Yuxian He<SUP>b</SUP> and Stefan P?hlmann<SUP>a</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Infection Biology Unit, German Primate Center, G?ttingen, Germany <SUP>b</SUP>Institute of Pathogen Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China <SUP>c</SUP>State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China <SUP>d</SUP>Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA <SUP>e</SUP>Department of Neurology, University of Texas School of Medicine at San Antonio, San Antonio, Texas, USA <SUP>f</SUP>Institute for Virology, Philipps University Marburg, Marburg, Germany
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.
FOOTNOTES
Received 3 October 2012. Accepted 24 January 2013.
Address correspondence to Stefan P?hlmann, s.poehlmann@dpz.eu.
Published ahead of print 6 February 2013
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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