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Species-specific remodelling of host cells in the most pathogenic malaria causing parasite Plasmodium falciparum

  • Full or part time
    Dr M Treeck
  • Application Deadline
    Saturday, November 23, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Moritz Treeck’s Group based at the Francis Crick Institute (the Crick).

The most severe form of human malaria is caused by the parasite Plasmodium falciparum. Its virulence is closely linked to the export of parasite proteins into its host cell, leading to an increase in rigidity and cytoadhesion of infected erythrocytes to endothelial cells, which obstructs blood flow to vital organs [1]. Unlike the other at least 4 human-infecting Plasmodium species, P. falciparum exports a family of 18 ‘FIKK’serine/threonine kinases of unknown function into the host cell [2-4]. We revealed substantial species-specific phosphorylation of erythrocyte proteins by P. falciparum, but not by Plasmodium knowlesi, which is not predicted to export any kinases (under review). By systematic deletion of all FIKK kinases combined with large-scale quantitative phosphoproteomics we identified unique phosphorylation fingerprints for each kinase, including phosphosites on parasite virulence factors and host cell proteins. For a subset of these kinases we could show that they are important in regulating cytoadherence of infected red blood cells to endothelial cells and are therefore important for pathogenesis. We have investigated one FIKK kinase in detail and identified a surface translocation phenotype of the key cytoadhesion ligand, but the specific function of the phosphorylation events mediated by this kinase is not understood. This project opens the possibility to investigate one or more of the other FIKK kinases and their role in malaria pathogenesis. This includes, but is not limited to study of the kinases itself using structural biology and inhibitor screens, but will also include gene editing on parasite and human proteins and the development of cellular assays to measure virulence traits in medium throughput.

Interestingly, not all FIKKs show a molecular phenotype in cell culture, that is, they may only be required in conditions met in the human host. We are also very interested to study the functions of FIKKs under conditions that mimic disease, and investigate their contribution to disease state in patient populations through collaborations with clinical researchers. A candidate interested this project will therefore either work on the molecular biology of these kinases, their role in disease, or a combination of both.

This is part of a large ongoing effort in the lab to characterize the species specific expansion of an effector kinase family in malaria parasites. We are interested in the molecular details of how these kinases function, what their targets are and how they regulate host cellular functions. However, these assays are predominantly targeted towards cell culture experiments and the group also has a high interest to study the function of these kinases in the interaction with the host, that is to understand their role in human infections. As these are two very different projects, candidates with either high interest and a background in biochemistry, molecular biology and cell biology, or candidates with interest in the genetics and genomics of this kinases family in patients are invited to apply. The latter requires interest in genetics, analysis of genome data and ideally immunology.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Maier, A. G., Rug, M., O'Neill, M. T., Brown, M., Chakravorty, S., Szestak, T., . . . Cowman, A. F. (2008)

Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes.

Cell 134: 48-61. PubMed abstract

2. Marti, M., Good, R. T., Rug, M., Knuepfer, E. and Cowman, A. F. (2004)

Targeting malaria virulence and remodeling proteins to the host erythrocyte.

Science 306: 1930-1933. PubMed abstract

3. Otto, T. D., Rayner, J. C., Böhme, U., Pain, A., Spottiswoode, N., Sanders, M., . . . Berriman, M. (2014)

Genome sequencing of chimpanzee malaria parasites reveals possible pathways of adaptation to human hosts.

Nature Communications 5: 4754. PubMed abstract

4. Nunes, M. C., Goldring, J. P. D., Doerig, C. and Scherf, A. (2007)

A novel protein kinase family in Plasmodium falciparum is differentially transcribed and secreted to various cellular compartments of the host cell.

Molecular Microbiology 63: 391-403. PubMed abstract



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