[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
A role for glycolipid biosynthesis in severe fever with thrombocytopenia syndrome virus entry
Mary Jane Drake, Benjamin Brennan, Kenneth Briley Jr, Stephen M. Bart, Eric Sherman, Agnieszka M. Szemiel, Madeleine Minutillo, Frederic D. Bushman, Paul Bates
Published: April 7, 2017 / http://dx.doi.org/10.1371/journal.ppat.1006316
A novel bunyavirus was recently found to cause severe febrile illness with high mortality in agricultural regions of China, Japan, and South Korea. This virus, named severe fever with thrombocytopenia syndrome virus (SFTSV), represents a new group within the Phlebovirus genus of the Bunyaviridae. Little is known about the viral entry requirements beyond showing dependence on dynamin and endosomal acidification. A haploid forward genetic screen was performed to identify host cell requirements for SFTSV entry. The screen identified dependence on glucosylceramide synthase (ugcg), the enzyme responsible for initiating de novo glycosphingolipid biosynthesis. Genetic and pharmacological approaches confirmed that UGCG expression and enzymatic activity were required for efficient SFTSV entry. Furthermore, inhibition of UGCG affected a post-internalization stage of SFTSV entry, leading to the accumulation of virus particles in enlarged cytoplasmic structures, suggesting impaired trafficking and/or fusion of viral and host membranes. These findings specify a role for glucosylceramide in SFTSV entry and provide a novel target for antiviral therapies.
As obligate, intracellular parasites, viruses depend upon numerous host-derived factors to replicate. For many bunyaviruses, these pro-viral host factors are largely uncharacterized. In the present study, we used an unbiased genetic screening strategy to identify human genes that facilitate the entry process of a newly discovered pathogenic bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV). Our screen and subsequent validation confirmed a role for the glucose-modified lipid, glucosylceramide (GlcCer), in the entry of SFTSV. We found that depletion of GlcCer in the cell leads to the accumulation of virus particles in membranous compartments, suggesting that the virions cannot properly access the cytoplasm to initiate replication. Clinically available compounds that target GlcCer formation may provide a novel antiviral therapeutic strategy for this newly emerged virus.
Citation: Drake MJ, Brennan B, Briley K Jr, Bart SM, Sherman E, Szemiel AM, et al. (2017) A role for glycolipid biosynthesis in severe fever with thrombocytopenia syndrome virus entry. PLoS Pathog 13(4): e1006316. doi:10.1371/journal.ppat.1006316
Editor: Sean P.J. Whelan, Harvard Medical School, UNITED STATES
Received: July 7, 2016; Accepted: March 24, 2017; Published: April 7, 2017
Copyright: © 2017 Drake et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (http://www.nih.gov/) grants AI052845 and AI082020 to FDB and T32AI007324-23 to MJD, National Institute of General Medicine Sciences (http://www.nih.gov/) grant T32GM007229-37 to MJD, Department of Defense Peer Reviewed Medical Research Program (http://cdmrp.army.mil/prmrp/) grant W81XWH-14-1-0204 to PB, and BB was supported by a Wellcome Trust Senior Investigator Award (No. 099220/Z/12/Z) to Richard M. Elliot. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Bunyavirus; SFTS.