Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses

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 t...

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Published inAmerican journal of respiratory cell and molecular biology Vol. 41; no. 3; pp. 339 - 347
Main Authors Thomas, Belinda J, Lindsay, Mandy, Dagher, Hayat, Freezer, Nicholas J, Li, Dongsheng, Ghildyal, Reena, Bardin, Philip G
Format Journal Article
LanguageEnglish
Published United States 01.09.2009
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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.
AbstractList 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.
Author Ghildyal, Reena
Lindsay, Mandy
Li, Dongsheng
Bardin, Philip G
Freezer, Nicholas J
Dagher, Hayat
Thomas, Belinda J
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Snippet Individuals with asthma are prone to viral and bacterial infections, and most asthma exacerbations have been linked to viruses, particularly rhinovirus. Excess...
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StartPage 339
SubjectTerms Adult
Asthma - immunology
Asthma - virology
Cell Death - physiology
Cell Differentiation - physiology
Cells, Cultured
Chemokines - immunology
Child
Fibroblasts - cytology
Fibroblasts - immunology
Fibroblasts - virology
Humans
Immunity, Innate - physiology
Interferon Regulatory Factor-3 - metabolism
Interferon Type I - immunology
Interleukin-8 - genetics
Interleukin-8 - metabolism
Neutrophils - immunology
Picornaviridae Infections - immunology
Respiratory Mucosa - cytology
Rhinovirus - physiology
Signal Transduction - physiology
Transforming Growth Factor beta1 - metabolism
Virus Replication - physiology
Title Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses
URI https://www.ncbi.nlm.nih.gov/pubmed/19168696
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