Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Abstract

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…A possible explanation for these results is the fact that we only measured virus release or RNA levels at 24 h. Changes in virus induced IFN at 24 h are unlikely to alter virus replication at 24 h, although we cannot exclude an effect on virus replication at later time points (Edwards et al. 2012b). Roflumilast was previously shown to suppress RSV infection at day 10 post infection using airway epithelial cells in air–liquid interface cultures (Mata et al.…”

Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations

“…IFN also up‐regulates the expression of RIG‐I, MDA5 and TLR3 in MCs suggesting increased detection of HRV by MCs 37. The demonstration that boosting IFN responses can protect human MCs from HRV infection is of significance, as bronchial epithelial IFN responses following HRV infection are impaired in moderate/severe asthma 16, 17, 19, 20. In addition, the localization of MCs in the bronchial epithelium increases with asthma severity suggesting that in severe asthma, MCs are at an increased risk of HRV infection and viral shedding.…”

“…IFNs induce a range of IFN‐stimulated genes (ISGs) via which they mediate their antiviral activities 15. Deficiencies in IFN production have been reported in bronchial epithelial cells and bronchoalveolar lavage macrophages from asthmatic subjects 16, 17, 18; however, this may relate to severity of disease 19, 20.…”

Dendritic Cells in Human Lung Disease

“…Following prolonged allergen avoidance, ongoing asthma symptoms are associated with persistently lower pDC expression of the ligand for the regulatory protein known as inducible costimulatory molecule (ICOS-L). Blood mononuclear cells from those with asthma generally produce less IFNα following viral activation in vitro; this appears to be most evident in those with severe asthma 31,33 and airway neutrophilia 34 , but may not be seen in milder asthma 35 . Deficient IFN production by blood leukocytes in asthma is likely to be a consequence of pDC dysfunction, though only a few studies have specifically examined purified pDC.…”