title: Respiratory Syncytial Virus Uses CX3CR1 as a Receptor on Primary Human Airway Epithelial Cultures.
abstract: Respiratory syncytial virus (RSV) is the most frequent cause of lower respiratory disease in infants, but no vaccine or effective therapy is available. The initiation of RSV infection of immortalized cells is largely dependent on cell surface heparan sulfate (HS), a receptor for the RSV attachment (G) glycoprotein in immortalized cells. However, RSV infects the ciliated cells in primary well differentiated human airway epithelial (HAE) cultures via the apical surface, but HS is not detectable on this surface. Here we show that soluble HS inhibits infection of immortalized cells, but not HAE cultures, confirming that HS is not the receptor on HAE cultures. Conversely, a "non-neutralizing" monoclonal antibody against the G protein that does not block RSV infection of immortalized cells, does inhibit infection of HAE cultures. This antibody was previously shown to block the interaction between the G protein and the chemokine receptor CX3CR1 and we have mapped the binding site for this antibody to the CX3C motif and its surrounding region in the G protein. We show that CX3CR1 is present on the apical surface of ciliated cells in HAE cultures and especially on the cilia. RSV infection of HAE cultures is reduced by an antibody against CX3CR1 and by mutations in the G protein CX3C motif. Additionally, mice lacking CX3CR1 are less susceptible to RSV infection. These findings demonstrate that RSV uses CX3CR1 as a cellular receptor on HAE cultures and highlight the importance of using a physiologically relevant model to study virus entry and antibody neutralization.
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Johnson
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Beth A
authors.initials: BA
authors.lastname: McNally
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Ioannidis
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Emilio
authors.initials: E
authors.lastname: Flano
authors.affiliation: Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Teng
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, Oklahoma, United States of America.
authors.forename: Antonius G
authors.initials: AG
authors.lastname: Oomens
authors.affiliation: School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Walsh
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Peeples
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D019707:Receptors, Chemokine / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*; D018113:Respiratory Syncytial Virus, Human / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019707:Receptors, Chemokine; D014764:Viral Proteins; D019204:GTP-Binding Proteins