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Bloomsbury PhD Studentship: Role of thrombospondin type1 repeat (TSR) domain proteins in motility and virulence of Babesia parasites


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Dr Ellen Knuepfer , Prof D Werling , Dr Rob Moon No more applications being accepted Funded PhD Project (UK Students Only)
London United Kingdom Cell Biology Epidemiology Genetics Molecular Biology Veterinary Sciences Parasitology Pathology

About the Project

Project Summary:

Babesiosis is a disease symptomatically very similar to malaria, caused by Babesia parasites infecting and multiplying in erythrocytes. Babesia and Plasmodium are closely-related protozoan parasites. Both are transmitted by insect vectors. Babesiosis affects a large range of vertebrates including livestock, companion animals, and also humans.

All symptoms of this disease, and onward transmission result from the cyclical invasion of host erythrocytes, and thus a better understanding of this process could yield vital new drug or vaccine candidates. Whereas this process is well-studied for malaria parasites, little is known about this process in Babesia. We know that proteins in micronemal organelles are required for host cell recognition and parasite motility. Thrombospondin type 1 repeat domain (TSR) proteins form an important group of micronemal proteins in Plasmodium and have critical roles in motility, invasion of salivary glands, hepatocytes and erythrocytes1. Some TSR-containing proteins recognise glycosaminoglycans on the host cell surface and at the same time connect to the actin-myosin motor through their cytoplasmic tail, generating the motility required for host cell invasion. One such example is the thrombospondin-related anonymous protein (TRAP). Four TSR-domain containing proteins can be identified in the B. divergens genome. Based on limited transcription profiling all four genes appear expressed in blood stages of Babesia. Three of these hypothetical proteins are secreted TSR-proteins, one of which is showing domain structures reminiscent of TRAP. We hypothesise that similar to Plasmodium, TSR-proteins are involved in and required for erythrocyte invasion of B.divergens. This project will study the role of B.divergens TSR-proteins in erythrocyte invasion to understand the steps leading to invasion. 

The projects main objectives are

  1. Confirm gene models and transcription profiles of all 4 genes encoding TSR-domain containing proteins during the blood cycle stage of B. divergens.
  2. Determine the essentiality/redundancy of each of these proteins during host cell invasion and their vaccine potential.
  3. Visualise the localisation of these potential parasite adhesins during invasion using real-time fluorescence microscopy.
  4. Identify host cell receptors on human and bovine erythrocytes. 

The project will utilise in vitro tissue culture systems established for B.divergens elsewhere in the world as well as genome editing methodology using CRSIPR/Cas92 followed by real-time fluorescence imaging techniques3. We will adapt existing CRISPR/Cas9 vectors to generate inducible gene knockouts, domain swaps or deletions and point mutations of essential TSR-proteins. Generating specific antibodies, we will test these in invasion inhibition experiments. Imaging of transgenic B.divergens parasites will pinpoint at which step of the invasion process these ligands act. Furthermore, the motility of free transgenic B.divergens parasites will be quantitated and potential host cell receptors characterised. 

This studentship will be held jointly between the labs of Ellen Knuepfer (RVC), who has strong background in reverse genetics using CRISPR/Cas9 tools including the development of inducible gene knockout technologies in Plasmodium4 and Robert Moon (LSHTM) who has recently established CRISPR-Cas9 in a zoonotic Plasmodium parasite and specialises in studying parasite invasion and motility using live-cell imaging approaches5 with further support by Prof Dirk Werling (RVC) who has a strong background in immunology. 

This project offers an exciting opportunity to work in two world-class research institutions with leading labs in the field of malaria, branching out newly into the field of babesiosis. Strong international collaborations exist with Oxford University, ITM Antwerp, Francis Crick Institute, the NY Blood Centre and University of Florida which will be able to provide further support.

 

Requirements

Essential

  • Must meet our standard PhD entry requirements
  • Successful degree in biological or veterinary sciences
  • Self-motivated
  • Good knowledge of molecular biology
  • Interest in infectious disease, cell and molecular biology

Desirable

  • Undergraduate and/or postgraduate research experience, especially in: tissue culture/sterile working techniques; molecular biology techniques.

 

This is a 3 year fully-funded studentship, open to applicants eligible for "Home" fees. International applicants are welcome to apply but must be able to fund the difference between "Home" and "Overseas" tuition fees. 

Please note that EU/EEA and Swiss national students may no longer be eligible for the “Home” rate of tuition fees, dependent on personal circumstances (including immigration status and residence history in the UK) and UK government rules which are currently being developed. For up-to-date information on fees for EU/EEA and Swiss national students following brexit please see our fees and funding page.

This project will start in October 2021, be lab-based and require work with human and/or bovine blood.

If you are interested in applying for this position, please follow the link below. Please use your personal statement to demonstrate any previous skills or experience relevant to the project.

 

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Interviews will take place March 2021.

We welcome informal enquiries - these should be directed to the Lead Supervisor: [Email Address Removed]

Deadline: 07/02/2021


Funding Notes

This is a 3 year fully-funded studentship, open to home applicants. International and EU students are welcome to apply but must be able to fund the difference between Home Fees and the international tuition fees.

References

1. Morahan, B. J., Wang, L. & Coppel, R. L. No TRAP, no invasion. Trends in Parasitology 25, 77–84 (2009).
2. Hakimi, H. et al. Genome Editing of Babesia bovis using the CRISPR/Cas9 System. mSphere 4, (2019).
3. Sevilla, E. et al. Kinetics of the invasion and egress processes of Babesia divergens, observed by time-lapse video microscopy. Scientific Reports 8, 14116 (2018).
4. Knuepfer, E., Napiorkowska, M., van Ooij, C. & Holder, A. A. Generating conditional gene knockouts in Plasmodium – a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9. Scientific Reports 7, 3881 (2017).
5. Yahata, K. et al. Gliding motility of Plasmodium merozoites. http://biorxiv.org/lookup/doi/10.1101/2020.05.01.072637 (2020).
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