title: Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses.
abstract: Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared.
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458.
authors.forename: Audrey Stéphanie
authors.initials: AS
authors.lastname: Richard
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458.
authors.forename: Adam
authors.initials: A
authors.lastname: Zhang
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458.
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458.
authors.forename: Min
authors.initials: M
authors.lastname: Zong
authors.affiliation: The Scripps Research Institute, Immunology and Microbial Sciences, Jupiter, FL 33458 hchoe@scripps.edu.
authors.forename: Hyeryun
authors.initials: H
authors.lastname: Choe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001430:Bacteriocins / Q000378:metabolism / Q000494:pharmacology; D003715:Dengue / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects / Q000502:physiology*; D029043:Ebolavirus / Q000187:drug effects / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000821:virology; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008566:Membranes / Q000187:drug effects; D051379:Mice; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D014771:Virion / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects; D014901:West Nile Fever / Q000821:virology; D014902:West Nile virus / Q000187:drug effects / Q000502:physiology*
chemical_list: D001430:Bacteriocins; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides; D010714:Phosphatidylethanolamines; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; C408123:phosphatidylserine receptor; C040522:duramycin; C483858:phosphatidylethanolamine
keywords: T-cell immunoglobulin mucin domain proteins; apoptotic mimicry; phosphatidylethanolamine; phosphatidylserine receptors; virus entry