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Title: SpyCEP interferes with the neutrophil response against Group A Streptococcus
Author: Lawrenson, Richard
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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This study examined how SpyCEP impaired the neutrophil response to Group A Streptococcus (GAS). It was known prior to this study that SpyCEP cleaved some of the neutrophil specific chemokines (Kurupati, et al. 2010, Zinkernagel, et al. 2008). These chemokines are known to have a variety of effects on neutrophil function, and the impact of SpyCEP on two specific effects, neutrophil homing to infection foci and NETosis, has been reported (Edwards, et al. 2005, Zinkernagel, et al. 2008). This study identified that the substrate range of SpyCEP included all known neutrophil specific chemokines. No other substrates were found. Furthermore, the relative cleavage rate of these chemokines by SpyCEP was determined, with the most potent, CXCL8, being the optimum substrate (Mukaida, et al. 1998). It was hypothesised that other effects of chemokines on neutrophils, not just neutrophil homing and NETosis, would also be ablated. Neutrophil release from the bone marrow stores is potentiated by chemokines. It was found that neutrophil release from the bone marrow was lower when mice were infected with SpyCEP-positive compared to SpyCEP-negative bacteria. Furthermore, lower levels of circulating chemokines were also found in mice infected with SpyCEP-positive GAS. Chemokines also play a role in the activation of neutrophils, and the upregulation of receptors involved in this process (Detmers, et al. 1990). This study identified that neutrophil phagocytosis of SpyCEP-positive bacteria was impaired compared to SpyCEP-negative bacteria. The neutrophils incubated with SpyCEP-positive bacteria were found to have less chemokine at their surface, and lower surface expression of a phagocytosis receptor, CR3. This receptor is known to be important for GAS phagocytosis (DeMaster, et al. 2002) providing a mechanism for this effect. This work has found several novel effects of SpyCEP on neutrophil function. These impairments take place throughout the neutrophil response to GAS infection.
Supervisor: Sriskandan, Shiranee Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available