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EASTBIO: The role of mannose exposure as a mechanism of ageing exploited by Plasmodium falciparum.

  • Full or part time
    Prof M A Vickers
    Dr A Rowe
    Prof H M Wilson
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Supervisors:

Professor Mark Vickers (University of Aberdeen)
https://www.abdn.ac.uk/people/m.a.vickers

Professor Alexandra Rowe (University of Edinburgh)
http://alexrowe.bio.ed.ac.uk/contact/

Professor Heather Wilson (University of Aberdeen)
https://www.abdn.ac.uk/ims/research/profiles/h.m.wilson

Malaria is a major health problem. There are over 200 million infections per year worldwide, with 1000 of these in the UK. The disease causes over 400,000 deaths per year (WHO Malaria report 2018). Resistance to currently used drugs is becoming a major problem. A multi-pronged approach is needed to combat the disease. A key area for investigation is the interaction of parasites with the human immune system. Malarial parasites have a complex life cycle, but the main site of replication is in red blood cells1. These provide a refuge from the adaptive immune system as they do not express MHC class I molecules. Immunity must therefore be provided by the innate immune system, particularly macrophages in the liver and spleen which ‘filter’ the blood.

We have identified a new system whereby high mannose glycans are exposed on aged cells, notably red blood cells that have been subject to accumulated oxidative stress and bind the mannose receptor on macrophages to mediate clearance. This mechanism of ageing is constitutively active in sickle cell disease, which is now the commonest single gene disorder in the UK and affects >20 million worldwide2. The disease has become so common because the carrier state confers protection against malaria3. In a highly productive collaboration with the Rowe lab, University of Edinburgh, we demonstrated infection of red blood cells by P. falciparum results in surface display of mannose and this is particularly true in cells from carriers of sickle cell disease. This therefore represents the first unified mechanism to explain both the advantageous and deleterious consequences of the sickle mutation.

Research hypotheses and aims
Human macrophages phagocytose P. falciparum infected red cells by recognising exposed mannose glycans and that this pathway can be targeted for therapeutic purposes.

Aim 1: to determine if macrophages recognise mannose on red blood cells infected with P. falciparum.
Aim 2: to test whether therapeutic macrophages can be ‘repurposed’ to treat malaria.

Methodology and Research training
The student will be trained in confocal and super-resolution microscopy to elucidate the pattern of mannoses exposed by infection with malaria. Clinical samples from patients with active malaria will be accessed from clinical haematology labs and mannose exposure in infected cells will be tested by flow cytometry following training. Macrophages will be manufactured using several techniques, including from induced pluripotential stem cells, with a particular emphasis on methods used by the Scottish Blood transfusion Service (SNBTS) in order to manufacture macrophages for other clinical trials. Parasites will be cultured and added to macrophages that have been optimised from the first year’s work. Supervisors have extensive experience in areas of macrophage biology, parasite infection and clinical haematology and are well placed to support the project training and goals. The research builds on work that is ongoing in the laboratories of the two host Institutes.

Application Procedure:
http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts and CV to Alison McLeod at . Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to .

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body. Queries on eligibility? Email Alison McLeod ().

Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.

References

1.Cowman, A., Healer, J., Marapana, D. and Marsh, K. (2016). Malaria: Biology and Disease. Cell, 167(3), pp.610-624.
2.Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573.
3.Williams, T., Mwangi, T., Wambua, S., Alexander, N., Kortok, M., Snow, R. and Marsh, K. (2005). Sickle Cell Trait and the Risk of Plasmodium falciparum Malaria and Other Childhood Diseases. The Journal of Infectious Diseases, 192(1), pp.178-186.



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