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Background: Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Methods: Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. Results: PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Conclusions: Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis. (Less)

SummaryBackground Rhinoviruses from the Enterovirus genus cause frequent infections and induce remarkably high titres of anticapsid antigen antibodies in asthmatics, while the prevalence of neutralising antibodies to the gut-trophic echoviruses from the same genus is diminished. Objective To assess the absolute and specific antibody titres to VP1 antigens of the gut-trophic enteroviruses, echovirus 30 and Sabin 1 poliovirus, in asthmatic and non-asthmatic children. Methods Recombinant polypeptides representing the VP1 capsid antigens of echovirus 30 and Sabin poliovirus 1 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n = 45) and non-asthmatic (n = 29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. Results The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls (P

Background: Exacerbations of asthma in children are frequently associated with rhinovirus (RV) infections and rhinovirus-induced wheeze in infancy is a predictor of the development of asthma. In contrast, there is evidence for an association of a reduced risk of childhood atopy and infection with echoviruses, a gut-trophic virus that, like rhinovirus, belongs to the Enterovirus genus. Aims: To assess the absolute and specific antibody titres to VP1 antigens of the lung-trophic rhinovirus and the gut-trophic echovirus in asthmatic and non-asthmatic children. Methods: Recombinant polypeptides representing the VP1 capsid antigens of all three RV species and echovirus 30 were produced. Their ability to bind IgG1 antibodies from the plasma of asthmatic (n=45) and non-asthmatic (n=29) children were quantitated by immunoassays that incorporated immunoabsorptions to remove cross-reactivity. Results: The IgG1 antibody titres and prevalence of antibody binding to echovirus 30 were significantly lower for asthmatic children compared to controls ( P < 0.05), and inversely correlated with total IgE levels for the whole study population ( r = -0.262; P < 0.05). Asthmatic children had higher total antibody binding to RV antigens compared to non-asthmatic controls and when species-specificity of the responses were dissected out, the high responses in asthmatics remained for the highly prevalent RV-A species. Conclusions: The associations of lower antibody titres of asthmatic children to echovirus and a heightened response to rhinovirus suggest a dichotomy where respiratory enterovirus infection/immunity increases the probability of developing asthma and enteric infections lower the risk.

Asthma exacerbations are associated with human rhinovirus (HRV) infections, and more severe exacerbations are associated with HRV-C. We have previously shown that the HRV-C-specific antibody response is low in healthy adult sera and that most of the antibody to HRV-C is cross-reactive with HRV-A.To compare the antibody response to each HRV species in asthmatic and nonasthmatic children in whom the type of HRV infection was known.Total and specific IgG₁ binding to HRV viral capsid protein antigens of HRV-A, -B, and -C were tested in the plasma from nonasthmatic children (n = 47) and children presenting to the emergency department with asthma exacerbations (n = 96). HRV, found in most of the children at the time of their exacerbation (72%), was analyzed using molecular typing.Asthmatic children had higher antibody responses to HRV. The titers specific to HRV-A, and to a lesser extent HRV-B, were higher than in nonasthmatic controls. The species-specific responses to HRV-C were markedly lower than titers to HRV-A and HRV-B in both asthmatic and nonasthmatic children (P.001). The titers both at presentation and after convalescence were not associated with the HRV genotype detected during the exacerbation.The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species.