title: AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus.
abstract: BACKGROUND
  The mosquito-borne Zika virus (ZIKV) is now recognized as a blood-borne pathogen, raising an important question about how the virus gets into human bloodstream. The imminent threat of the ZIKV epidemic to the global blood supply also demands novel therapeutics to stop virus transmission though transfusion.
  
  
  OBJECTIVE
  We intend to characterize ZIKV tropism for human endothelial cells (ECs) and provide potential targets for intervention.
  
  
  RESULTS
  We conducted immunostaining, plaque assay, and quantitative reverse transcription-polymerase chain reaction of ZIKV RNA to evaluate the possible infection of ECs by ZIKV. Both the African and the South American ZIKV strains readily infect human umbilical vein endothelial cells and human ECs derived from aortic and coronary artery, as well as the saphenous vein. Infected ECs released infectious progeny virus. Compared with the African strains, South American ZIKV isolates replicate faster in ECs and are partially cytopathic, suggesting enhanced virulence of these isolates. Flow cytometric analyses showed that the susceptibility of ECs positively correlated with the cell surface levels of tyrosine-protein kinase receptor UFO (AXL) receptor tyrosine kinase. Gain- and loss-of-function studies further revealed that AXL is required for ZIKV entry at a postbinding step. Finally, small-molecule inhibitors of the AXL kinase significantly reduced ZIKA infection of ECs.
  
  
  CONCLUSIONS
  We identified EC as a key cell type for ZIKV infection. These data support the view of hematogenous dissemination of ZIKV and implicate AXL as a new target for antiviral therapy.
authors.affiliation: From the Center for Infectious Diseases, Discovery Biology, SRI International, Harrisonburg, VA (S.L., T.T.W.); and Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (L.J.D., B.E.I.).
authors.forename: Shufeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: From the Center for Infectious Diseases, Discovery Biology, SRI International, Harrisonburg, VA (S.L., T.T.W.); and Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (L.J.D., B.E.I.).
authors.forename: Leon J
authors.initials: LJ
authors.lastname: DeLalio
authors.affiliation: From the Center for Infectious Diseases, Discovery Biology, SRI International, Harrisonburg, VA (S.L., T.T.W.); and Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (L.J.D., B.E.I.).
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.affiliation: From the Center for Infectious Diseases, Discovery Biology, SRI International, Harrisonburg, VA (S.L., T.T.W.); and Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (L.J.D., B.E.I.). tony.wang@sri.com.
authors.forename: Tony T
authors.initials: TT
authors.lastname: Wang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000821:virology*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014709:Vero Cells; D000071244:Zika Virus / Q000187:drug effects / Q000201:enzymology*; D000071243:Zika Virus Infection / Q000201:enzymology*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000813:Anilides; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: Zika virus; axl receptor tyrosine kinase; blood; endothelial cells; infection; virus internalization