Investigating the fundamental biology and pharmacology of liver-stage malaria parasites.

The 2024/25 application process is now closed

Visit the MRC DTP/CASE at LSTM pages for further information

This proposed Ph.D. research aims to advance our understanding of the fundamental biology of liver-stage malaria parasites, with a specific focus on elucidating the mechanisms governing the reactivation of hypnozoites. Building upon a decade of pioneering work by the Liverpool malaria team, the study will delve into the intricacies of malaria parasite biology, particularly in the liver stage, where dormant hypnozoites persist and contribute to relapse infections.

A crucial facet of the investigation will involve an in-depth exploration of the pharmacology of 8-aminoquinolines, the exclusive class of antimalarial drugs known for their efficacy in achieving radical cure for relapse malaria. The research will endeavour to unravel the molecular mechanisms underlying the action of these drugs.

The Ph.D. programme will leverage cutting-edge technologies, incorporating newly established liver spheroid and liver organoid microphysiological systems (MPS). These innovative platforms will provide a more physiologically relevant environment, allowing for exploration of host-parasite interactions during the liver stage of infection.

The interdisciplinary nature of this research is reflected in the comprehensive training components offered within the Ph.D. programme. Trainees will gain proficiency in cell and molecular biology, pharmacology, high-content imaging, and advanced transcriptomic technologies such as RNAseq and nano-string. Bioinformatics will be a key focus, enabling the integration and interpretation of complex datasets arising from multi-omics approaches and there will also be an opportunity to develop skills in AI and machine-learning.

Recognising the value of global collaboration, the Ph.D. programme will offer opportunities for overseas training and work placements with both academic and non-academic partners, including industry. This collaborative approach aims to foster a holistic understanding of malaria biology and accelerate the translation of research findings into impactful interventions. Ultimately, this Ph.D. proposal aspires to contribute significantly to the field of malaria research, addressing critical gaps in knowledge and paving the way for novel therapeutic strategies against relapse malaria.

 

Where does the project lie on the Translational Pathway?

T1 – Basic Research

Expected Outputs
  • New fundamental knowledge relating to hyponozoite reactivation e.g. primary data publication
  • New fundamental knowledge relating to 8-aminoquinoline pharmacology e.g. primary data publication
  • Training opportunities and placement opportunities

 

Training Opportunities
  • AI
  • Bioinformatics
  • High-content imaging
  • Nano-string/RNA seq
  • MPS/Organoid generation

 

Skills Required

The successful research PhD candidate will possess analytical skills for data interpretation, and effective communication abilities. Adaptability and problem-solving capabilities will be crucial for overcoming challenges in the research process. Collaboration and teamwork skills will facilitate effective engagement in the interdisciplinary research environment of this project. Ethical and professional integrity will be required to underpin responsible research conduct.

Key Publications associated with this project

Camarda, G., Jirawatcharadech, P., Priestley, RS., Ahmed Saif, A., March, S., Wong, MHL., Leung, S., Miller, AB., Baker, DA., Alano, PA.,  Paine, MJ., Bhatia, SN., O’Neill, PM., Ward, SA.,, Biagini GA,*.  Antimalarial activity of primaquine operates via a two-step biochemical relay Nature Comms. (2019) 10: DOI: 10.1038/s41467-019-11239-0

 

Voorberg-van der Wel AM, Zeeman AM, Nieuwenhuis IG, van der Werff NM, Klooster EJ, Klop O, Vermaat LC, Kumar Gupta D, Dembele L, Diagana TT, Kocken CHM. A dual fluorescent Plasmodium cynomolgi reporter line reveals in vitro malaria hypnozoite reactivation. Commun Biol. 2020 Jan 3;3:7. doi: 10.1038/s42003-019-0737-3. PMID: 31909199; PMCID: PMC6941962.

 

Mellin R, Boddey JA. Organoids for Liver Stage Malaria Research. Trends Parasitol. 2020 Feb;36(2):158-169. doi: 10.1016/j.pt.2019.12.003. Epub 2019 Dec 14. PMID: 31848118.

 

Vantaux A, Péneau J, Cooper CA, Kyle DE, Witkowski B, Maher SP. Liver-stage fate determination in Plasmodium vivax parasites: Characterization of schizont growth and hypnozoite fating from patient isolates. Front Microbiol. 2022 Sep 23;13:976606. doi: 10.3389/fmicb.2022.976606. PMID: 36212849; PMCID: PMC9539820.

 

Vantaux A, Péneau J, Cooper CA, Kyle DE, Witkowski B, Maher SP. Liver-stage fate determination in Plasmodium vivax parasites: Characterization of schizont growth and hypnozoite fating from patient isolates. Front Microbiol. 2022 Sep 23;13:976606. doi: 10.3389/fmicb.2022.976606. PMID: 36212849; PMCID: PMC9539820.