PhD student profiles

     
     
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Heledd Davies
Wellcome Trust 4-year Interdisciplinary PhD Programme, beginning in Autumn 2012

Project title
The Role of Exported Malaria Parasite Proteins in Pathogenesis

Principle investigator: Dr Andrew Osborne, ISMB, Birkbeck and UCL
Co-investigator: Dr Kostas Thalassinos, ISMB, Birkbeck and UCL

 
Background

Before joining the ISMB I studied chemistry at the University of Liverpool, graduating with an MChem in 2012. My degree led me into a variety of disciplines: a physical chemistry third year project using scanning tunnelling microscopy with Dr. Rasmita Raval; an inorganic materials based summer project with Dr. Andrew Fogg and concluding with my dissertation project investigating the mechanism of action of endoperoxide antimalarials with Professor Paul O’Neill. This involved both an organic synthesis component as well as a cell biology aspect at the Liverpool School of Tropical Medicine. It was this experience working with malaria that confirmed my interest in transferring my chemical training to the biological field, and the interdisciplinary nature of the ISMB’s Structural, Computational and Chemical Biology course provided the perfect opportunity to do so.

 
Rotation projects

Rotation 1 (Dr Sanjib Bhakta)
Evaluation of Novel Tetrahydroisoquinolines Targeting the MurE enzyme for the Treatment of Tuberculosis

Rotation 2 ( Dr Andrew Martin)
Computational Analysis of Antibody Crystal Structures: A Study of Conformational Changes on Binding

Rotation 3 (Dr Andrew Osborne)
Novel Malaria proteins targeting the Periphery of the Host Red Blood Cell (selected for PhD project)

 
PhD Project

My decision to pursue a PhD project in the field of malaria was fuelled by the intriguing complexity of the plasmodium parasite’s interactions with its host, much of which has yet to be explained. As it resides insides the red blood cell during the asexual stage of its life cycle, the parasite exports a number of proteins into the host cell, modifying it according to its needs. My project is focused on changes that occur at the periphery of the red blood cell, by proteins which modulate the rigidity of the erythrocyte cytoskeleton or cause the cells to adhere to the endothelium. Many of these changes are essential for the parasite to evade the host immune system by blocking infected erythrocytes within the circulatory system to prevent clearance by the spleen. These processes are also responsible for the symptoms of the malaria disease, and a greater understanding of the mechanisms involved would facilitate the challenge of developing much-needed new anti-malarial treatments.

Using a combination of microscopy and protein expression techniques I have identified a number of novel sequences which target this area of the infected host red blood cell. I intend to further characterise these interactions by developing new assaying methods and utilising biophysical techniques, with the goal of gaining a greater understanding of how these host-modifying proteins work together and how this relates to the pathogenicity of the malaria parasite.

 
figure 1
 
Figure: A human red blood cell infected with the malaria parasite expresses a GFP-tagged malarial protein which is exported into the host cell and localises in a ring at the periphery of the red blood cell.
 
Publications

Guzman J D, Pesnot T, Barrera D A, Davies H M, McMahon E, Evangelopoulos D, Mortazavi P N, Munshi T, Maitra A, Lamming E D, Angell R, Gershater M C, Redmond J M, Needham D, Ward J M, Cuca L E, Hailes H C and Bhakta S ‘Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase’ (2015) Journal of Antimicrobial Chemotherapy, published online February 4 2015 ahead of print

 

 

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