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β2 integrin LFA1 mediates airway damage following neutrophil trans-epithelial migration during RSV infection

Herbert, JA; Deng, Y; Hardelid, P; Robinson, E; Ren, L; Moulding, D; Smyth, RL; (2020) β2 integrin LFA1 mediates airway damage following neutrophil trans-epithelial migration during RSV infection. European Respiratory Journal , 56 , Article 1902216. 10.1183/13993003.02216-2019. Green open access

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Abstract

RSV bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease and no specific anti-viral treatment. Using a novel in vitro primary trans-epithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil trans-epithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage, reduced ciliary beat frequency, but also a reduction in infectious viral load. Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β2 integrin LFA-1) for intracellular adhesion molecule-1 (ICAM-1) on epithelial cells reduced neutrophil adherence to RSV infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils which migrated or prevent the reduction in infectious viral load. These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative pre-clinical model that will further elucidate mechanisms that drive disease severity and has utility in anti-viral drug discovery.

Type: Article
Title: β2 integrin LFA1 mediates airway damage following neutrophil trans-epithelial migration during RSV infection
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1183/13993003.02216-2019
Publisher version: https://doi.org/10.1183/13993003.02216-2019
Language: English
Additional information: Copyright ©ERS 2020 This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10094176
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