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Title: Helminth-derived inhibitors of the IL-33 pathway
Author: Vacca, Francesco
ISNI:       0000 0004 8497 9999
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Allergic asthma is a chronic inflammatory disease of the airways characterised by type 2 immune responses in the lungs. Increased mucus production, airway hyperresponsiveness and eosinophilia are the main features of the asthmatic lung, and they are caused by an increased production of IL-5 and IL-13. A strong inducer of these cytokines is the alarmin IL-33 that it is released upon necrotic death of epithelial cells. IL-33 can be released in the lung due to damage caused by inhalation of proteolytic allergens, parasite migration or respiratory viral infection. IL-33 activates several immune cell populations such as mast cells, TH2 lymphocytes and type 2 Innate Lymphoid cells (ILC2s). Parasitic infection is associated with a decreased risk of developing allergic immune responses, and this prevention appears to be mediated by the release of immunomodulatory excretory/secretory products (ES). The aims of this project are to study ES products from the intestinal murine nematode Heligmosomoides polygyrus (HES), and in particular identifying and characterising single proteins that interfere with the IL-33 pathway. HES administration has been shown to suppress both IL-33 and ST2 (the IL-33 receptor) in a mouse model of asthma. Therefore parasites may suppress the development of allergic asthma via the secretion of soluble mediators. Firstly, before the beginning of this project, a single protein from HES was identified as suppressor of IL-33: the H. polygyrus Alarmin Release Inhibitor (HpARI). Through direct binding assay, HpARI was shown to bind directly to the active cytokine, blocking IL-33- ST2 interaction. In vitro HpARI suppressed the release of IL-5 and IL-13 in response to IL-33. In vivo, administration of HpARI in an asthma model using the fungal allergen Alternaria alternata reduces ILC2s activation and eosinophilic inflammation. Next, type 2 inflammation was analysed in a neonatal model of RSV infection. Respiratory viral infections during childhood have been associated with increased risk of asthma development later in life, especially in those infant hospitalised with severe RSV bronchiolitis. In a neonatal mouse model of RSV infection IL-33 play an important role for the development of type 2 immune responses. In our model, RSV infection in neonates induces activation of lung ILC2s 24h post-infection. When HpARI was co-administered with RSV, ILC2 activation was suppressed at primary RSV infection, and at RSV reinfection in later life. A trend for reduced viral titre was observed when HpARI was co-administered with RSV suggesting that HpARI might interfere with viral infectivity. Finally, the next focus of the project was identifying a novel single protein involved in the suppression of ST2. Fractionation of HES was used to identify a novel protein which in recombinant form suppresses ST2. We named this novel protein H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI). HpBARI is a CCP domain-containing protein that suppresses IL-33 responses in vitro and in vivo. Using ELISA, direct binding assay and surface plasmon resonance, I showed that HpBARI binds directly to ST2 and that this interaction prevents IL-33 from binding to its receptor, blocking initiation of type 2 immune responses. These two newly identified parasite proteins, HpARI and HpBARI, both interfere with the IL-33 pathway. HpARI and HpBARI are related proteins as they each consist of 3 or 2 CCP domains, respectively, and they give insight into how parasites can immune modulate the host immune system.
Supervisor: McSorley, Henry ; Schwarze, Jurgen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Heligmosomoides polygyrus ; HpARI ; HpBARI ; inflammatory responses ; asthma