title: A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection.
abstract: Rift Valley fever virus (RVFV) causes recurrent insect-borne epizootics throughout the African continent, and infection of humans can lead to a lethal hemorrhagic fever syndrome. Deep mutagenesis of haploid human cells was used to identify host factors required for RVFV infection. This screen identified a suite of enzymes involved in glycosaminoglycan (GAG) biogenesis and transport, including several components of the cis-oligomeric Golgi (COG) complex, one of the central components of Golgi complex trafficking. In addition, disruption of PTAR1 led to RVFV resistance as well as reduced heparan sulfate surface levels, consistent with recent observations that PTAR1-deficient cells exhibit altered Golgi complex morphology and glycosylation defects. A variety of biochemical and genetic approaches were utilized to show that both pathogenic and attenuated RVFV strains require GAGs for efficient infection on some, but not all, cell types, with the block to infection being at the level of virion attachment. Examination of other members of the Bunyaviridae family for GAG-dependent infection suggested that the interaction with GAGs is not universal among bunyaviruses, indicating that these viruses, as well as RVFV on certain cell types, employ additional unidentified virion attachment factors and/or receptors.
  
  
  OBJECTIVE
  Rift Valley fever virus (RVFV) is an emerging pathogen that can cause severe disease in humans and animals. Epizootics among livestock populations lead to high mortality rates and can be economically devastating. Human epidemics of Rift Valley fever, often initiated by contact with infected animals, are characterized by a febrile disease that sometimes leads to encephalitis or hemorrhagic fever. The global burden of the pathogen is increasing because it has recently disseminated beyond Africa, which is of particular concern because the virus can be transmitted by widely distributed mosquito species. There are no FDA-licensed vaccines or antiviral agents with activity against RVFV, and details of its life cycle and interaction with host cells are not well characterized. We used the power of genetic screening in human cells and found that RVFV utilizes glycosaminoglycans to attach to host cells. This furthers our understanding of the virus and informs the development of antiviral therapeutics.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Riblett
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Blomen
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lucas T
authors.initials: LT
authors.lastname: Jae
authors.affiliation: Diagnostic Systems Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA.
authors.forename: Louis A
authors.initials: LA
authors.lastname: Altamura
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Jason.Wojcechowskyj@ucsf.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wojcechowskyj
mesh_terms: D002460:Cell Line; D005820:Genetic Testing; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016296:Mutagenesis; D012296:Rift Valley fever virus / Q000502:physiology*; D053585:Virus Attachment
chemical_list: D019812:Heparan Sulfate Proteoglycans