The Bloomsbury Colleges | PhD Studentships | Studentships 2016 | Combining reverse genetics and three-dimensional electron microscopy to dissect malaria parasite invasion of red blood cells (LSHTM) & (BBK)
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Combining Reverse Genetics and Three-dimensional Electron Microscopy to Dissect Malaria Parasite Invasion of Red Blood Cells

Principle Supervisor: Dr Robert W. Moon (LSHTM)

Co-Supervisor: Professor Helen Saibil (Bbk)

Malaria is caused by protozoan parasites of the genus Plasmodium and remains one of the most important infectious diseases of man. Clinical malaria is associated with cycles of parasite invasion and multiplication within red blood cells (RBCs).  Malaria parasites produce a range of adhesive proteins enabling them to bind to the surface of RBCs and invade them. These parasite proteins can determine disease severity and which hosts are susceptible, as well as presenting important targets for vaccine design. This project will investigate the role of these parasite adhesins during the process of red blood cell invasion in Plasmodium knowlesi, a simian malaria parasite which causes severe zoonotic malaria infections in humans in South-east Asia.

The project will use a P. knowlesi strain that has been adapted to in vitro culture with human red blood cells, which is highly amenable to genetic manipulation. A range of reverse genetics approaches will be used to examine the function parasite adhesins, including gene knock-outs and fluorescent tagging of parasite proteins. In a cross disciplinary approach transgenic parasite lines will be analysed using a range of cutting edge imaging techniques including electron and X-ray tomography, to allow the process of invasion to be examined in unparalleled detail. The process of RBC invasion is highly conserved amongst malaria parasites, but poorly understood, so the project will provide a clearer understanding of invasion in all malaria parasite species and potentially aid the development of new therapeutic interventions for an emergent zoonotic malaria parasite.

Candidate Requirements

The selected candidate will require a strong undergraduate degree (1st Class or 2.1) in a biological sciences related subject, together with a general understanding of molecular biology. They should have a keen interest in infectious disease research, cell imaging and molecular biology.  This studentship will be held between the labs of Robert Moon (LSHTM), who established the P. knowlesi culture and transfection system in human RBC (Moon et al 2013), and Helen Saibil (Birkbeck) a global leader in the study of macromolecular machines using 3D electron microscopy. It will therefore offer the opportunity for the student to gain critical skills and insight in the two distinct specialist areas of molecular parasitology and advanced 3D electron microscopy. This specialist training and the novelty of the system will also provide plentiful opportunities for independent innovation. The student will be provided with training in the culture and genetic manipulation of human malaria parasites, including the use of genome editing tools (CRISPR-Cas9 system). They will also learn and develop techniques for the preparation and imaging of parasite samples for electron and x-ray tomography and correlative microscopy, including high-pressure freezing, freeze substitution and sectioning of samples.

The studentship project will be carried out within the context of a broader 5-year research programme to determine the function of P. knowlesi adhesins which will also include key collaborations at the Francis Crick Institute, Oxford University and Imperial College London. The student will be provided the opportunity to present their work at both national and international conferences and will be expected to publish resultant work in high impact papers in open access peer-reviewed journals. The studentship is open to Home/EU students as the studentship only covers fees at the Home/EU rate.

Key References

Bannister, L.H., et al., Structure and invasive behaviour of Plasmodium knowlesi merozoites in vitro. Parasitology, 1975. 71(3):483-91.

Cowman, A.F. and B.S. Crabb, Invasion of Red Blood Cells by Malaria Parasites. Cell, 2006. 124(4):755-766.

Moon, R.W., et al., Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes. PNAS, 2013. 110(2):531-536.

Singh, B., et al., A large focus of naturally acquired Plasmodium knowlesi infections in human beings. The Lancet, 2004. 363(9414):1017-1024.

Watermeyer. J. M., et al., A Spiral Scaffold Underlies Cytoadherent Knobs in

Plasmodium falciparum-Infected Erythrocytes. Blood, 2015. DOI: http://dx.doi.org/10.1182/blood-2015-10-674002

Further details about the project may be obtained from:

Principle Supervisor:

Dr Robert W. Moon

Immunity and Infection Department

Faculty of Infectious and Tropical Diseases

London School of Hygiene and Tropical Medicine

Keppel Street, London WC1E 7HT

Rob.moon@lshtm.ac.uk

02079272743

Co-Supervisor:

Professor Helen Saibil

Crystallography

Department of Biological Sciences

ISMB

Birkbeck College

London WC1E 7HX, UK

h.saibil@mail.cryst.bbk.ac.uk

02076316820

Further information about PhDs at LSHTM is available from:

http://www.lshtm.ac.uk/study/research/

Application forms and details about how to apply are available from:

http://www.lshtm.ac.uk/study/research/itd_mphilphd.html

Please contact Robert Moon, rob.moon@lshtm.ac.uk, or Helen Saibil, h.saibil@mail.cryst.bbk.ac.uk, with general queries; or scholarships@lshtm.ac.uk for queries related to the submission of the application form.

Please use the standard LSHTM application form to apply for this studentship and state clearly under the funding section that you are applying for this particular studentship. Since you are applying for an existing project you don't need to include a research proposal, so please instead upload a document which states that you are applying for this studentship.

Closing date for this application:

Wednesday 10th February 2016