Presence of neutrophils in the lungs prior to infection with respiratory virus alters disease severity in mice
File(s)
Author(s)
Owen, Amber
Type
Thesis
Abstract
Respiratory viruses such as respiratory syncytial virus (RSV) and influenza A viruses (IAV) are amongst the leading causes of global death by communicable disease. Certain individuals, including infants and the elderly are at increased risk of severe disease following respiratory viral infection. However, the immunologic factors underlying increased risk are not fully understood. Using human challenge studies, increased neutrophil activation in the nasal mucosa before experimental RSV infection was found to best correlate with developing symptomatic disease. Similarly, in mouse models of RSV infection, intranasal CXCL1 to recruit neutrophils shortly before RSV infection drove exacerbated disease. In this thesis, mouse models were used to further explore how neutrophils in the respiratory tract before respiratory viral infection can alter the immune response and subsequent disease. Firstly, intranasal exposure to bacteria or their PAMPs before RSV infection was shown to increase early weight loss. This was not driven solely by neutrophils in the lungs before infection but by elevated expression of Il1a and Tnfa. Secondly, by increasing the time between neutrophil recruitment and RSV infection, this was shown to result in opposing effects on disease, protecting mice from weight loss. This was associated with the presence of apoptotic neutrophils and potentially through them altering the alveolar macrophage response to the virus. Finally, it was shown that neutrophils recruited by intranasal CXCL1 at different timepoints could exacerbate or protect mice from weight loss following IAV infection. By comparing the RSV and IAV infection models, it was revealed that the timepoint of neutrophil recruitment relative to recognition of the virus, rather than the timepoint of infection, likely dictates disease outcomes. Together, these findings increase our understanding of the environmental and immunologic factors that increase risk of severe disease following respiratory viral infection and might help in the development of future broad-spectrum interventions.
Version
Open Access
Date Issued
2024-03-08
Date Awarded
01/07/2024
License URL
Advisor
Johansson, Cecilia
Sponsor
Wellcome Trust (London, England)
Grant Number
102126/B/13/Z
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)