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Title: Investigating the role of SOCS1 in asthma exacerbations
Author: Strong, Katherine
ISNI:       0000 0005 0287 1819
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Asthma exacerbations are frequently caused by respiratory viral infection, most commonly rhinoviruses, in up to 80% of cases. Virus-induced asthma exacerbations have been associated with increased type 2 airway inflammation and impaired interferon induction, however the mechanisms driving virus-induced asthma exacerbations are not well understood. Suppressor of cytokine signalling 1 (SOCS1) is an inhibitor of both interferon signalling and induction and is induced by the cytokines IL-4 and IL-13. This thesis sought to investigate if SOCS1 expression is increased in asthmatic bronchial epithelial cells and if SOCS1 is associated with impaired interferon responses or worse symptoms upon rhinovirus infection. In bronchial biopsies from atopic asthmatics, SOCS1 expression was associated with worse symptoms and greater falls in lung function upon rhinovirus infection. However, in cultured bronchial epithelial cells, there was no difference in SOCS1 mRNA expression between atopic asthmatics or healthy controls. In bronchial biopsies and cultured bronchial epithelial cells, skin prick test positivity was associated with increased SOCS1 expression and induction, respectively. This thesis has also shown that IL-4 and rhinovirus interact to increase SOCS1 expression; IL-4 induces SOCS1 via activation of the adjacent promoter, while rhinovirus functions through a distinct and uncharacterised mechanism, which may involve distal regulatory elements. The knockout of SOCS1 in a fibroblast cell line enhanced rhinovirus-induced interferon induction. However, this thesis was unable to demonstrate a role for nuclear SOCS1 in inhibiting rhinovirus-induced interferon or determine if IL-4 or rhinovirus increases the nuclear localisation of SOCS1. Collectively, these findings support the hypothesis that increased SOCS1 is associated with worse clinical outcome following rhinovirus infection. These findings support a role for increased type 2 inflammation in enhancing SOCS1 expression, which may be of interest in asthma exacerbations. The identification of the precise mechanism by which SOCS1 is induced and undergoes nuclear localisation will require further study.
Supervisor: Edwards, Michael ; Lavender, Paul ; Johnston, Sebastian Sponsor: Asthma UK Centre in Allergic Mechanisms of Asthma
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral