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Title: Structure and function of the VAL family in Brugia malayi and Heligmosomoides polygyrus
Author: Murray, Janice
ISNI:       0000 0004 5948 8290
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2015
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Evasion of an immune response mounted by a host is fundamental to the survival of a parasite. Immune evasion can be mediated in many ways from the production of molecules by the parasite which mimic cytokines produced by the human immune system to hiding from the immune system by locating within host cells. The production of immune cell mediating molecules in excretory secretory products is another means by which the parasite can tailor its surroundings to facilitate prolonged survival. The hypothesis of immunosuppression by parasite products, in particular members of the Venom Allergen Like (VAL) family, is key to this thesis. VAL proteins are members of the much larger SCP/TAPS family, which covers proteins from parasitic helminths such as Heligmosomoides polygyrus (H.polygyrus)to the free-living nematode Caenorhabditis elegans. These nematodes may have one or more genes encoding proteins that contain the SCP/TAPS domains often choosing to express these proteins at critical points within the helminths lifecycle. Phylogenetic analysis of a selection of these proteins revealed that their classification could be determined based upon the number of SCP/TAPS domains. Alternatively the presence or absence of the signal sequence combined with conserved cysteine residue data could be used. Further investigations into possible functions of the VAL proteins from H.polygyrus were carried out using recombinant protein produced in an insect cell expression system. To further examine the function of VAL genes a system that allows the heterologous expression of a gene in the well-documented Leishmania infection setting was employed. In vitro and in vivo studies were carried out which examined various infection parameters. Parasite infectivity in bone marrow derived macrophages in vitro along with cytokine production was observed. In vivo the development of lesions and subsequent parasite recovery from infected mice gave indications of changes in virulence that could be attributed to the presence and expression of the HpVAL genes. The ability of parasites to ameliorate symptoms of allergic and autoimmune diseases is now well documented with the most extreme use of this knowledge resulting in administration of an active parasitic infection as a treatment regime. We hope to identify individual molecules from a parasite that is known to reduce allergic symptoms in the allergic airway inflammation (AAI) model and produce these in a more structured and regulated fashion. It is plausible that VAL proteins from H.polygyrus may possess these regulatory properties, as has been shown for the excretory secretory products (HES) of the parasite; to that end HpVAL-1 and HpVAL-4 were tested in the allergic airway inflammation model and were shown to reduce both cell numbers in the bronchioalveolar lavage fluid and eosinophilia. Finally, the position of the parasite and products secreted by the parasite was examined. Directly labelled HES and recombinant VAL proteins were used to identify binding sites inside the parasite and within the parasites’ locality in the host i.e. the gut. Confocal microscopy revealed binding of HES to the parasites surface and internal structures and of both HES and HpVAL-4 to goblet cells and Paneth cells inside the gut. Paneth cells may affect parasite survival by influencing the gut microbiota and goblet cells have been shown to influence parasite persistence by production of mucus. Thus HES and more specifically HpVAL proteins may, through their interactions with these cells, interfere with mechanisms employed by the host to expel the parasite.
Supervisor: Maizels, Rick; Macdonald, Andrew; Aebischer, Toni Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Heligmosomoides polygyrus ; helminth ; immune evasion