Yanaika Sabogal Pineros

Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease.

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA‐rich mucus plugs are characteristic features of severe RSV–LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first‐line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti‐viral effect in vitro. Second, we studied NET formation in vivo during severe RSV–LRTD in infants and bovine RSV–LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV–LRTD. Detailed histopathological examination of calves with RSV–LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV–LRTD contributes to airway obstruction. Copyright

Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA‐rich mucus plugs are characteristic features of severe RSV–LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first‐line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti‐viral effect in vitro. Second, we studied NET formation in vivo during severe RSV–LRTD in infants and bovine RSV–LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV–LRTD. Detailed histopathological examination of calves with RSV–LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV–LRTD contributes to airway obstruction. Copyright

Interferon-induced epithelial response to rhinovirus-16 in asthma relates to inflammation and FEV1

Bronchial epithelial cells from mild asthma patients in response to in vivo rhinovirus-16 challenge, display a marked interferon-induced response 6 days post-infection, which correlates with eosinophilic inflammation and virus-induced decline of lung function.

IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity

Background Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL‐33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. Objective We hypothesized that IL‐33 is necessary to drive asthma exacerbations. We intervened with the IL‐33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL‐33 in the airways and IL‐33–dependent mechanisms that underlie severe asthma exacerbations. Methods Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL‐33 receptor ST2, anti–TSLP, or both. Results We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL‐33 during virus‐driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL‐33 and not TSLP was necessary to drive exacerbations. IL‐33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN‐&bgr; expression and prevent the TH1‐promoting dendritic cell phenotype. IL‐33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response. Conclusion Interventions targeting the IL‐33/ST2 axis could prove an effective acute short‐term therapy for virus‐induced asthma exacerbations. Graphical abstract Figure. No Caption available.

IL33 and TSLP involvements in influenza-induced exacerbation in a murine model of chronic asthma

Introduction: Viral airway infections cause acute worsening of asthma symptoms and additional accumulation of inflammatory cell subsets in the airways. Here we aimed to dissect the innate immune response that might underlie virus-induced exacerbations in an adequate murine model of exacerbating asthma. Methods: Mice were sensitized i.n. to HDM extract for 5 days/week for 5 consecutive weeks. On day 29 mice were infected with low dose of influenza A/X31; 3 day before and after the virus infection the animals have been treated with anti TSLP and IL33 receptors (T1/ST2 and TSLPR, respectively) mAbs. The airways cellular influx was assessed, cytokines were measured in BALF, lung function and histology were determined in different time points after infection. Results: Infected sensitized mice infected showed an exacerbation of allergic inflammation as reflected by a prolonged AHR and a boosted inflammatory influx into the airways, in comparison to infected non-sensitized mice. As an early event upon influenza infection, sensitized mice showed the induction of IL-33 and TSLP paralleled by the increased influx into the airways of ILC2, basophils, NK and NKT cells. Blocking the effect of IL-33 and TSLP using anti T1/ST2 and TSLPR mAbs the NKT cells, basophils, ILC2 recruitments into the airways were attenuated; the eosinophilic and neutrophilic influxes were reduced in BALF. Conclusions: Influenza infection of sensitized mice boosted the induction of crucial effectors of the innate immune response, leading the worsening of a broad inflammatory response into the airways. Limiting IL33 and TSLP can dampen airway inflammation and virus-induced changes in HDM-sensitized mice.