Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Abstract

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-␤, even though both groups responded to synthetic dsRNA with similar levels of IFN-␤ expression. Exogenous IFN-␤ was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-␤ 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 epithelialderived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations.

Interactions between the Bronchial Epithelium and Fibrocytes in the Pathogenesis of Airway Remodeling in Asthma

“…The time-course of allergen-induced fibrocytes accumulation and frequency of a -SMA+ fibrocytes are consistent with more recently reported observations on the accumulation of fibroblast-and myofibroblast-like cells of undefined origin and phenotype in similarly allergen-exposed asthmatic individuals [25]. Moreover, certain functional characteristics of fibrocytes [32,40,41] are remarkably similar to those reported for bronchial fibroblast-and myofibroblast-like cells directly isolated from asthmatic airways [42,43], including the pattern of cytokine production, the in-vitro susceptibility to viral infections and the response to viral stimulation.…”

Virus-Infected Human Mast Cells Enhance Natural Killer Cell Functions

“…6 b). In contrast, Reo-NHLF demonstrated substantial IL-8 (210.8 ± 150.1 normalized mRNA expression, n = 4) and IL-6 (45.1 ± 13.7 normalized mRNA expression, n = 3) gene expression compared to Mock-NHLF (3.1 ± 1.2 and 6.7 ± 0.5, respectively), similarly to previous findings [30] . Reovirus-infected Calu-3 cells also demonstrated low type I IFN mRNA responses ( fig.…”

Rhinovirus and dsRNA Induce RIG-I-Like Receptors and Expression of Interferon β and λ1 in Human Bronchial Smooth Muscle Cells

“…Exposure to RV also results in fibroblast and BSMC production of proinflammatory cytokines [27], [31]. However, findings in human cultured airway fibroblasts indicate that this cell type does not contribute significantly to RV-induced antiviral responses [31].…”

“…A series of separate experiments were performed in which BSMCs were infected with RV1B grown in Ohio HeLa cells (European Collection of Cell Cultures) as previously described [31]. RV1B in different levels of multiplicity of infection (MOI), 0.05–0.5 MOI, were used to infect BSMCs for 1 h at room temperature with shaking.…”