title: Role of human TLR4 in respiratory syncytial virus-induced NF-κB activation, viral entry and replication.
abstract: TLRs play a key role in innate immune defenses. It was previously reported that purified respiratory syncytial virus (RSV) fusion protein elicits an inflammatory response in hematopoietic cells, which required expression of TLR4 and its co-receptor CD14. However, a biological role of TLR4 in immunity to RSV, as initially proposed, has remained inconclusive and controversial. Here, we directly assess the role of human TLR4 and its co-receptors in NF-κB activation, viral entry and replication using intact virions rather than purified RSV components. We used HEK 293 reporter cells that are highly permissive for RSV and that either express or a lack a functional human TLR4/MD-2/CD14 complex. We demonstrate that RSV-mediated NF-κB activation, viral entry and replication are independent of the expression of a functional human TLR4/MD-2/CD14 complex and that, in turn, human TLR4 activation by LPS remains unaffected in RSV-infected cells. Thus, although isolated viral compounds such as purified RSV F protein may bind TLR4 and/or CD14, a direct interaction between intact RSV particles and the human TLR4 receptor complex does not seem to play a biological role in RSV pathogenesis.
authors.affiliation: Department of Pediatrics, University of British Columbia and the Child & Family Research Institute, Vancouver, Canada. nmarr@cfri.ca
authors.forename: Nico
authors.initials: N
authors.lastname: Marr
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000472:pathogenicity / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000235:genetics; D014760:Viral Fusion Proteins / Q000276:immunology; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: C526850:F protein, human respiratory syncytial virus; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014760:Viral Fusion Proteins