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Title: Properties and function of Heligmosomoides polygurus secreted apyrases
Author: Berkachy, Rita
ISNI:       0000 0004 8504 620X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Helminth parasite secreted molecules have been shown to modulate the host immune system to the extent of alleviating symptoms of immune disorders such as allergy and autoimmunity. Apyrases secreted by helminth parasites have potential immunoregulatory functions. They constitute a family of nucleotide-metabolising enzymes which can disturb purinergic signalling pathways of immune cells via hydrolysing inflammatory ATP released following tissue damage. In this thesis, the biochemical properties of the five apyrases secreted by the intestinal nematode Heligmosomoides polygyrus were elucidated via heterologous expression in the yeast Pichia pastoris. Results showed that the enzymes belonged to a group of calcium-dependent apyrases with a broad optimum pH and a broad substrate specificity, catalysing the hydrolysis of both nucleoside tri- and diphosphates. In an attempt to understand if any immune modulation was displayed by apyrases, in vivo studies were performed. Apyrase-1 and -3 were expressed in Trypanosoma musculi, a suitable in vivo vehicle for the expression of genes encoding secreted proteins of nematode parasites. Among the results shown, the transgenes grew faster compared to control trypanosomes, and splenocytes from mice infected with T. musculi expressing Apy-3 produced higher levels of IL-5 and IL-13. Both immunological and physiological factors appear to be responsible for these changes, suggesting that apyrases might modulate the immune response in addition to influencing the availability of extracellular purines for salvage by parasites. The effect of H. polygyrus secreted apyrases on type 2 immunity was also examined in this thesis during an acute model of allergic inflammation and during nematode infection. Intranasal administration of recombinant Apy-1 and Apy-3 did not seem to have an effect in regulating immunological responses, at least in the models tested. Further work is required to probe the precise function of apyrases secreted by parasitic nematodes and the possible immune modulatory effects exerted by these enzymes.
Supervisor: Gounaris, Kleoniki Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral