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Title: The role of IL-15 in response to rhinovirus infections
Author: Jayaraman, Annabelle Tan
ISNI:       0000 0004 2724 622X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Rhinoviruses (RV) cause the common cold and are major precipitants of asthma exacerbations. The underlying mechanisms of RV-induced airways disease are unclear. IL-15 is a proinflammatory cytokine produced during viral infections and plays a key role in the regulation of NK cells. Using mouse models of RV infection and RV-induced asthma exacerbation we examined the role of IL-15 and its importance for NK cell responses during RV infections in allergic and non-allergic airways. We demonstrate RV-induced IL-15 upregulation in the airway and lungs of BALB/c mice at day 1 after infection and accumulation of NK cells in the airway and lungs at days 1-2 and 2-4 respectively. The NK cells exhibited an activated phenotype characterised by upregulated CD69, IFN-γ and GranzymeB expression. Blocking IL-15 upon intranasal administration of an IL-15 neutralising antibody inhibited the NK cell response to RV infection, which was associated with deficient IFN-γ production and increased expression of Th2 mediators. IL-15Rα knockout mice lack NK cells and also demonstrated deficient IFN-γ and increased Th2 responses to RV infection; these mice also exhibited deficient CD8+ T cell responses and an increased viral load. Similar results were observed in RV infected IFNAR1 ko mice, which was associated with deficient IL-15 upregulation. We suggest that RV-induced IL-15 is mediated by type I interferon signalling, and is necessary for NK cell responses and early IFN-γ production during RV-1B infection, which drives development of appropriate Th1 antiviral responses. In the absence of this pathway, Th2 responses result and are associated with impaired antiviral immunity. To examine the interaction between allergen driven Th2 immunity and RV infection, we employed a RV-induced asthma exacerbation model. Unexpectedly, RV infected allergen challenged mice, despite having increased viral load, demonstrated increased IL-15 expression and NK cell responses, revealing a novel interaction between allergic responses and antiviral immunity.
Supervisor: Johnston, Sebastian ; Stanciu, Luminita ; Bartlett, Nathan Sponsor: Imperial College
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral