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Title: Regulation of virus induced inflammation by type I interferons
Author: Goritzka, Michelle
ISNI:       0000 0004 6420 9540
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Type I interferons (IFNs) are the first line of defence against viral pathogens. They play a crucial role in activating antiviral responses to limit viral replication and viral spread. Human respiratory syncytial virus (RSV) can cause severe lung inflammation and this has been associated with polymorphisms in several innate immune response genes, including many that control the IFN system. In order to elucidate the importance of type I IFNs in regulating local inflammatory responses in the lung, their role in pulmonary immune responses to RSV infection was assessed in mice lacking the type I IFN receptor (Ifnar1-/-). Levels of proinflammatory cytokines and chemokines were markedly reduced during RSV infection. Similar results were obtained when in Ifnar1-/- mice were challenged with non-infectious innate stimuli such as Toll-like receptor agonists. It was further shown that the administration of recombinant IFN-α together with innate stimuli was sufficient to potentiate the proinflammatory cytokine production. Exploiting a reporter mouse strain expressing GFP under the control of the Ifna6 promoter, alveolar macrophages (AMs) were identified as the predominant source of type I IFNs during RSV infection. This type I IFN production solely relied on signalling through the cytosolic RIG-I-like receptors (RLRs), as AMs lacking MAVS, the adaptor downstream of RLRs, were unable to produce type I IFNs. Furthermore, Mavs-/- mice showed compromised production of proinflammatory cytokines and chemokines, and as a consequence had an increased viral burden and RSV-induced pathology. Interestingly, Mavs-/- mice had a marked deficiency in the production of monocyte chemoattractants and recruitment of inflammatory monocytes (infMo). The administration of recombinant CCL2 during RSV infection permitted monocyte recruitment into the lung of Mavs-/- mice and mediated an unexpected antiviral activity and reduced disease severity. This work emphasises a role for type I IFNs in antiviral immune responses by driving early proinflammatory cytokine responses and recruitment of antiviral monocytes, a yet underappreciated novel cell type responsible for dampening RSV-disease burden in vivo.
Supervisor: Johansson, Cecilia ; Edwards, Michael ; Openshaw, Peter Sponsor: National Heart and Lung Institute Foundation ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral