title: Induction and Antagonism of Antiviral Responses in Respiratory Syncytial Virus-Infected Pediatric Airway Epithelium.
abstract: Airway epithelium is the primary target of many respiratory viruses. However, virus induction and antagonism of host responses by human airway epithelium remains poorly understood. To address this, we developed a model of respiratory syncytial virus (RSV) infection based on well-differentiated pediatric primary bronchial epithelial cell cultures (WD-PBECs) that mimics hallmarks of RSV disease in infants. RSV is the most important respiratory viral pathogen in young infants worldwide. We found that RSV induces a potent antiviral state in WD-PBECs that was mediated in part by secreted factors, including interferon lambda 1 (IFN-λ1)/interleukin-29 (IL-29). In contrast, type I IFNs were not detected following RSV infection of WD-PBECs. IFN responses in RSV-infected WD-PBECs reflected those in lower airway samples from RSV-hospitalized infants. In view of the prominence of IL-29, we determined whether recombinant IL-29 treatment of WD-PBECs before or after infection abrogated RSV replication. Interestingly, IL-29 demonstrated prophylactic, but not therapeutic, potential against RSV. The absence of therapeutic potential reflected effective RSV antagonism of IFN-mediated antiviral responses in infected cells. Our data are consistent with RSV nonstructural proteins 1 and/or 2 perturbing the Jak-STAT signaling pathway, with concomitant reduced expression of antiviral effector molecules, such as MxA/B. Antagonism of Jak-STAT signaling was restricted to RSV-infected cells in WD-PBEC cultures. Importantly, our study provides the rationale to further explore IL-29 as a novel RSV prophylactic.
  
  
  OBJECTIVE
  Most respiratory viruses target airway epithelium for infection and replication, which is central to causing disease. However, for most human viruses we have a poor understanding of their interactions with human airway epithelium. Respiratory syncytial virus (RSV) is the most important viral pathogen of young infants. To help understand RSV interactions with pediatric airway epithelium, we previously developed three-dimensional primary cell cultures from infant bronchial epithelium that reproduce several hallmarks of RSV infection in infants, indicating that they represent authentic surrogates of RSV infection in infants. We found that RSV induced a potent antiviral state in these cultures and that a type III interferon, interleukin IL-29 (IL-29), was involved. Indeed, our data suggest that IL-29 has potential to prevent RSV disease. However, we also demonstrated that RSV efficiently circumvents this antiviral immune response and identified mechanisms by which this may occur. Our study provides new insights into RSV interaction with pediatric airway epithelium.
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry, and Biomedical Sciences, Queens University Belfast, Belfast, Northern Ireland.
authors.forename: Rémi
authors.initials: R
authors.lastname: Villenave
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry, and Biomedical Sciences, Queens University Belfast, Belfast, Northern Ireland.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Broadbent
authors.affiliation: The Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland.
authors.forename: Isobel
authors.initials: I
authors.lastname: Douglas
authors.affiliation: The Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Lyons
authors.affiliation: The Regional Virus Laboratory, Belfast Trust, Belfast, Northern Ireland.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coyle
authors.affiliation: Joy McCann Culverhouse Airway Disease Research Center, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Teng
authors.affiliation: Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry, and Biomedical Sciences, Queens University Belfast, Belfast, Northern Ireland.
authors.forename: Liam G
authors.initials: LG
authors.lastname: Heaney
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry, and Biomedical Sciences, Queens University Belfast, Belfast, Northern Ireland The Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shields
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry, and Biomedical Sciences, Queens University Belfast, Belfast, Northern Ireland u.power@qub.ac.uk.
authors.forename: Ultan F
authors.initials: UF
authors.lastname: Power
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D006801:Humans; D007223:Infant; D007372:Interferons; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D053612:Janus Kinases / Q000276:immunology; D064547:Myxovirus Resistance Proteins / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D050791:STAT Transcription Factors / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014709:Vero Cells; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D053612:Janus Kinases; D064547:Myxovirus Resistance Proteins; D050791:STAT Transcription Factors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579071:MX1 protein, human; C579068:MX2 protein, human