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Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma¹

Allergy and Inflammation Research, Division of Infection, Inflammation, and Repair, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom

Human rhinoviruses (HRV) are a major cause of asthma exacerbations and hospitalization. Studies using primary cultures suggest that this may be due to impaired production of type I and type III IFNs by asthmatic bronchial epithelial cells. Although epithelial cells are the main target for HRV infection, HRV can be detected in the subepithelial layer of bronchial mucosa from infected subjects by in situ hybridization. Therefore, we postulated that submucosal fibroblasts are also involved in the innate antiviral response to HRV infection in asthma. We found that regardless of subject group, bronchial fibroblasts were highly susceptible to RV1b infection. IL-8 and IL-6 were rapidly induced by either HRV or UV-irradiated virus, suggesting that these responses did not require viral replication. In contrast, RANTES expression was dependent on viral replication. Regardless of disease status, fibroblasts did not respond to HRV infection with significant induction of IFN-β, even though both groups responded to synthetic dsRNA with similar levels of IFN-β expression. Exogenous IFN-β was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-β expression. Their susceptibility to infection may cause them to be a reservoir for HRV replication in the lower airways, especially in asthmatic subjects where there is reduced protection offered by epithelial-derived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Medical Research Council (U.K.) Capacity Building Studentship (to N.B.) and the Asthma, Allergy, and Inflammation Research Charity (U.K.).

² Address correspondence and reprint requests to Prof. Donna Davies, Allergy and Inflammation Research, Level F South Block (810), Southampton General Hospital, Southampton, SO16 6YD, U.K. E-mail address: donnad{at}soton.ac.uk

³ Abbreviations used in this paper: HRV, human rhinovirus; BEC, bronchial epithelial cell; CPE, cytopathic effect; FEV, forced expiratory volume in 1 s; HASM, human airway smooth muscle; LDH, lactate dehydrogenase; MOI, multiplicity of infection; poly(I:C), polyinosinic-polycytidylic acid; p.i., postinfection; qPCR, quantitative PCR; RV, rhinovirus; RV1b, rhinovirus-1b; vRNA, viral RNA.

⁴ The online version of this article contains supplemental material.