title: Neural stem cell-derived exosomes mediate viral entry.
abstract: BACKGROUND
  Viruses enter host cells through interactions of viral ligands with cellular receptors. Viruses can also enter cells in a receptor-independent fashion. Mechanisms regarding the receptor-independent viral entry into cells have not been fully elucidated. Exosomal trafficking between cells may offer a mechanism by which viruses can enter cells.
  
  
  METHODS
  To investigate the role of exosomes on cellular viral entry, we employed neural stem cell-derived exosomes and adenovirus type 5 (Ad5) for the proof-of-principle study.
  
  
  RESULTS
  Exosomes significantly enhanced Ad5 entry in Coxsackie virus and adenovirus receptor (CAR)-deficient cells, in which Ad5 only had very limited entry. The exosomes were shown to contain T-cell immunoglobulin mucin protein 4 (TIM-4), which binds phosphatidylserine. Treatment with anti-TIM-4 antibody significantly blocked the exosome-mediated Ad5 entry.
  
  
  CONCLUSIONS
  Neural stem cell-derived exosomes mediated significant cellular entry of Ad5 in a receptor-independent fashion. This mediation may be hampered by an antibody specifically targeting TIM-4 on exosomes. This set of results will benefit further elucidation of virus/exosome pathways, which would contribute to reducing natural viral infection by developing therapeutic agents or vaccines.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA ; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Sims
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Gu
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Krendelchtchikov
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA ; Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Qiana L
authors.initials: QL
authors.lastname: Matthews
mesh_terms: D000256:Adenoviridae / Q000378:metabolism / Q000472:pathogenicity; D000818:Animals; D055354:Exosomes / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000821:virology; D053586:Virus Internalization
chemical_list: D008565:Membrane Proteins; C500399:TIM-4 protein, mouse
keywords: TIM-4; adenovirus type 5; neural stem cell-derived exosomes; phospholipids; viral entry