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Transforming Growth Factor-β Enhances Rhinovirus Infection by Diminishing Early Innate Responses

¹ Departments of Respiratory and Sleep Medicine, Medicine and Surgery, Monash Medical Centre; ² Monash Institute of Medical Research; ³ Monash University Centre for Inflammatory Diseases; and ⁴ Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia

Correspondence and requests for reprints should be addressed to Philip Bardin, FRACP, Ph.D., Department of Respiratory and Sleep Medicine, Monash Medical Centre, 246 Clayton Rd., Clayton, Victoria 3168, Australia. Email: Philip.bardin{at}southernhealth.org.au

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)-β 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-β1 and in myofibroblasts. Primary culture fibroblasts were pretreated with TGF-β1 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-β1 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-β1 appeared to be mediated via actions on IFN regulatory factor-3 pathways. These data demonstrate that TGF-β1 mediates enhanced virus replication and proinflammatory responses in airway cells. TGF-β may act as an endogenous immunosuppressant promoting virus replication and inflammation during the evolution of acute severe asthma associated with rhinovirus infection.

Key Words: TGF-β1 • rhinovirus • fibroblast • myofibroblast • asthma

CLINICAL RELEVANCE Transforming growth factor (TGF)-β is increased in asthma and may suppress immune responses. It is unknown whether TGF-β activity may impact on rhinovirus infections and play a role in virus-associated asthma exacerbations. TGF-β mediates enhanced rhinovirus replication probably via its suppressive actions on host type I interferon responses.