AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses.
Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Audrey Stéphanie
AS
Richard
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Byoung-Shik
BS
Shim
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Young-Chan
YC
Kwon
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110.
Rong
R
Zhang
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Yuka
Y
Otsuka
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Kimberly
K
Schmitt
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458.
Fatma
F
Berri
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110.
Michael S
MS
Diamond
Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, FL 33458; hchoe@scripps.edu.
Hyeryun
H
Choe
D000818:Animals; D002460:Cell Line; D003716:Dengue Virus / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007313:Insecta; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008831:Microcephaly / Q000821:virology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020365:RNA Helicases / Q000302:isolation & purification; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000302:isolation & purification; D017361:Viral Nonstructural Proteins / Q000302:isolation & purification; D053586:Virus Internalization; D014902:West Nile virus / Q000502:physiology; D000071244:Zika Virus / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D000071243:Zika Virus Infection / Q000473:pathology* / Q000821:virology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020365:RNA Helicases; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
AXL; Flaviviruses; Zika virus; fetal endothelial cell; placental barrier