Palor, Machaela Chelseah Co; (2024) Developing an animal-free in vitro model of the human air-blood barrier to study immune cell translocation and to test new therapies against viral lung infection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Respiratory syncytial virus (RSV) is a leading cause of childhood lower respiratory tract infection (LRTI) and hospitalisation worldwide. In infants with severe RSV bronchiolitis, excessive neutrophilic inflammation of the airways is a common pathological feature. Yet, the contribution of neutrophils to host defence and/or disease remains to be elucidated. Animal models of RSV bronchiolitis such as the rat and mouse provide ineffective systems for predicting clinical performance in man and thus limit developments in this area of drug discovery. In this project, an animal-free in vitro model of the human air-blood barrier comprising differentiated paediatric bronchial epithelial cells (BECs) and endothelial cells (EnCs) was employed to investigate neutrophil behaviour and function during RSV infection. Our results demonstrated that the rapid migration of neutrophils across RSV-infected co-cultures was associated with enhanced CD11b expression on migrated (airway side) neutrophils, as well as higher levels of myeloperoxidase (MPO) and neutrophil elastase (NE) on basolateral (blood side) neutrophils as a consequence of reverse migration (N = 12 neutrophil donors). The increased expression of MPO and NE were confirmed in peripheral blood neutrophils of infants admitted with RSV (N = 5 neutrophil donors). Antiviral treatment reduced viral load in RSV-infected co-cultures but did not affect MPO and NE expression (N = 6 neutrophil donors). Our findings highlight the physiological relevance of this neutrophil trans-endothelial epithelial migration (TEEM) model in replicating key human disease outcomes during RSV bronchiolitis, and thus its application in the study of underlying mechanisms that mediate inflammation and disease severity. They also emphasise the possibility of developing effective therapeutic strategies that are directed at host factors that contribute to disease pathogenesis, such as neutrophils, alongside viral targets.

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