Nematode parasites are expert manipulators of the immune response, allowing their persistence in their hosts. By determining the molecular basis of parasite immunomodulation, we can learn how to better modulate immune responses, prevent inflammation-induced diseases of ageing, and derive new strategies for combatting these important human and livestock parasites.
Complement control protein (CCP) domains occur in many, diverse, vertebrate proteins and are implicated in numerous biological functions. They are especially common in proteins of the innate immune system, and often mediate protein-protein interactions. They generally occur in tandem repeats joined by short linkers. Every nematode studied (both parasitic and non-parasitic) produce at least a few CCP domain-containing proteins, but this protein family has undergone a dramatic expansion in Heligmosomoides polygyrus, a nematode parasite of mice.
H. polygyrus has mastered immune evasion through secretion of immunomodulatory proteins. Recently, two such proteins were identified: HpTGM, which activates the TGF- pathway, and HpARI, which inhibits IL-33 responses . Significantly, both proteins consist of a series of CCP domains. Recent work in the McSorley lab identified a third immunomodulatory CCP protein (unpublished) and further analysis revealed the presence of many other secreted CCP proteins from this organism. We shall address the question of whether these proteins collectively represent an important, previously unrecognised armoury of parasite immunomodulators.
The PhD candidate will first learn how to use bioinformatic techniques to mine the genome of H. polygyrus, as well as human and livestock-infective parasitic nematodes. They will thus assemble the definitive list of parasite CCP domain-containing proteins. They will then use our validated protocols to recombinantly produce representative members of the family and test these (along with previously-expressed CCP proteins of known and unknown function) for known and novel immunomodulatory activities. Through a collaboration with MedImmune , the student will gain experience with further in vitro immune assays, including cytokine stimulation of innate lymphoid cells, T cells, macrophages and mast cells. Furthermore, MedImmune’s expertise in the design of cytokine-blocking antibodies will allow comparison of relative efficacy of parasite-derived and monoclonal antibody reagents.
Novel proteins with activity in these assays, alongside known immunomodulators such as HpARI, will be further investigated to identify mechanism of action, binding partners and structural characteristics. Structural work will be carried out using crystallography and NMR. Prof Barlow, an expert in CCP domain structural characterisation , will provide the appropriate training.
Functional and structural information will be combined to generate hypotheses in respect of functional sites and mechanisms that can then be tested through expression of point mutants and further assessments of activity.
Thus this project will assess the functional diversity of a novel family of proteins which are critical in host-parasite interactions. It will equip the students with valuable skills in bioinformatics, recombinant protein production, structural characterisation, and immunology. We expect the project to reveal novel strategies for immune evasion and furnish biochemical tools for further research.
 Osbourn, …, McSorley, 2017, Immunity, 47:739 doi:10.1016/j.immuni.2017.09.015.
 Cohen, 2015, Nat Commun, 6:8327 doi:10.1038/ncomms9327.
 Herbert, …, Barlow, 2015, J. Immunol, 195: 4986 doi:10.4049/jimmunol.1501388.