title: Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses.
abstract: Individuals with asthma are prone to viral and bacterial infections, and most asthma exacerbations have been linked to viruses, particularly rhinovirus. Excess transforming growth factor (TGF)-beta present in asthmatic airways may cause immune suppression, as well as transdifferentiate fibroblasts to myofibroblasts, thereby augmenting proinflammatory responses after rhinovirus infection. After rhinovirus infection we examined virus replication and host cell immune responses in airway fibroblasts in the presence of TGF-beta1 and in myofibroblasts. Primary culture fibroblasts were pretreated with TGF-beta1 or transdifferentiated into myofibroblasts, and then infected with rhinovirus. Viral replication, virus release, chemokine production, and interferon (IFN) responses were measured over 72 hours. Rhinovirus replication and virus release into supernatants were enhanced in fibroblasts incubated with TGF-beta1 and in fibroblasts obtained from patients with asthma. Myofibroblasts also showed more rhinovirus replication, and infected myofibroblasts produced excess neutrophil chemokines. Examination of innate responses revealed blunting of type I IFN reactions with dissociated viral RNA and IFN mRNA responses. Addition of type I IFN restituted antiviral responses, and the effect of TGF-beta1 appeared to be mediated via actions on IFN regulatory factor-3 pathways. These data demonstrate that TGF-beta1 mediates enhanced virus replication and proinflammatory responses in airway cells. TGF-beta may act as an endogenous immunosuppressant promoting virus replication and inflammation during the evolution of acute severe asthma associated with rhinovirus infection.
authors.affiliation: Departments of Respiratory and Sleep Medicine, Medicine and Surgery, Monash Medical Centre, Clayton, Victoria 3168, Australia.
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Thomas
authors.forename: Mandy
authors.initials: M
authors.lastname: Lindsay
authors.forename: Hayat
authors.initials: H
authors.lastname: Dagher
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Freezer
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Li
authors.forename: Reena
authors.initials: R
authors.lastname: Ghildyal
authors.forename: Philip G
authors.initials: PG
authors.lastname: Bardin
mesh_terms: D000328:Adult; D001249:Asthma / Q000276:immunology / Q000821:virology; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology; D002648:Child; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D010850:Picornaviridae Infections / Q000276:immunology*; D020545:Respiratory Mucosa / Q000166:cytology; D012229:Rhinovirus / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D018925:Chemokines; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016209:Interleukin-8; D053773:Transforming Growth Factor beta1