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Neutrophils in respiratory syncytial virus infection

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Title: Neutrophils in respiratory syncytial virus infection
Authors: Kirsebom, Freja
Item Type: Thesis or dissertation
Abstract: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections, especially in infants. In clinical studies of RSV infection, neutrophils have long been implicated as drivers of disease severity as they make up the vast majority of the cellular composition of the airways of infants hospitalised with severe disease. Furthermore, a transcriptomic analysis found that genes related to neutrophil function were over-expressed in infants hospitalised with severe RSV infections. Although airway neutrophilia is a hallmark of severe RSV disease, the mechanisms underlying neutrophil recruitment and activation in the lung are not yet well understood. Furthermore, it is unclear whether airway neutrophilia during RSV infection contributes to viral control and/or drives disease severity. Mechanistic studies into the role of neutrophils during RSV infection in murine and bovine models of disease have suggested that neutrophils may release NETs in response to RSV but whether this causes lung pathology in a manner which affects the outcome of disease is unknown. In these studies, the innate immune signalling pathways underlying neutrophil recruitment and activation in RSV-infected mice were investigated. MyD88/TRIF signalling was found to be essential for lung neutrophil recruitment while MAVS signalling, leading to type I IFN production, was necessary for neutrophil activation. Furthermore, antibody mediated neutrophil depletion was used to investigate the role of neutrophils during RSV infection. Neutrophils were not required for the production type I interferons (IFNs) in response to RSV, nor did neutrophils contribute to viral control. Neutrophil depletion also demonstrated that neutrophil recruitment during primary RSV infection was not required for the formation of memory T cell responses during RSV re-challenge. Neither neutrophil removal nor the enhancement of airway neutrophilia, by administration of the chemoattractant CXCL1 following RSV infection, affected disease severity as measured by weight loss. However, increased airway neutrophilia pre-infection, as established by administration of CXCL1, enhanced disease severity as measured by weight loss during RSV infection. This was associated with an enhanced recruitment of CD8+ T cells to the lung at the peak of disease. This study found that two distinct pathogen sensing pathways must collaborate for neutrophil recruitment and activation during RSV infection. Furthermore, although neutrophil recruitment in response to RSV does not appear to drive disease in mice, pre-existing infections or conditions which heighten airway neutrophilia may contribute to disease severity during RSV infection.
Content Version: Open Access
Issue Date: Jul-2019
Date Awarded: Mar-2020
URI: http://hdl.handle.net/10044/1/96404
DOI: https://doi.org/10.25560/96404
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Johansson, Cecilia
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: 109058/Z/15/Z
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses



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