Mechanistic origins of cell organisation and architecture underlying parasite functions
In my lab, we use the flagellated eukaryotic parasites Trypanosoma brucei and Leishmania mexicana to understand the fundamental processes that define the cell organisation underlying parasite interactions with their hosts and vectors. The distinctive shape of trypanosomes and Leishmania is formed by a corset of cross-linked microtubules that are just beneath the cell membrane and both have a flagellum that provides the propulsive force enabling them to move. We focus on understanding the morphogenesis of cytoskeletal-membrane interfaces that contribute to i) cell and substrate attachments, ii) interaction with the insect vector and mammalian host. To do this we use a range of modern molecular cell biology techniques combined with both light end electron microscopy.
The diseases - leishmaniasis and trypanosomiasis
Both Leishmania and trypanosomes have a complex life cycle in which they are transmitted by an insect vector between mammalian hosts. Leishmania causes a range of different diseases from the severe and fatal visceral leishmaniasis to the self-healing cutaneous leishmaniasis and is found throughout the tropics and into the southern Mediterranean. Trypanosoma brucei on the other hand is restricted to sub-Saharan Africa, where it causes the fatal disease African sleeping sickness.
Research group membership
UoA5: Biomedicine, Cell and Developmental Biology
Research grants and awards
Wellcome Trust, Collaborative Award – £2.3M (£337,000 to Oxford Brookes University), Apr 2021 – Mar 2026
Collaborative Award with Dr Eva Gluenz (University of Glasgow), Dr Richard Wheeler (University of Oxford), and Prof Jeremy Mottram (University of York) to define the molecular determinants required for Leishmania life cycle progression and virulence.
Royal Society, Newton International Fellowship - £99,000, Jun 2020 – May 2022
Post-doc fellowship for Brazilian researcher to study trypanosome flagellum assembly
Japan Society for Promotion of Science Overseas Fellowship - £90,000, Apr 2020 – Mar 2022
Post-doc fellowship for Japanese researcher to study Leishmania substrate attachment
Royal Society Research Grant - £17,800, Mar 2019 – Feb 2020
Identifying the molecular determinants of the interaction between the Leishmania metacyclic form and its host and vector
OBU GCRF Visiting Fellow Scheme – £7000, Aug 2018 – Oct 2018
To train visiting Brazilian post-doc in advanced techniques for the genetic manipulation of trypanosomatids
Wellcome Trust Biomedical Resource Grant - £709,168, Jan 2016 – Jan 2019
Genome scale genetic tagging and protein localisation in Trypanosoma brucei
co PI with Samuel Dean, Richard Wheeler, Mark Carrington, Sue Vaughan, Christiane Hertz-Fowler and Keith Gull
i) Assembly of cell-to-cell and cell-to-substrate attachment structures
The attachment of cells to either other cells or substrates is a fundamental attribute of eukaryotic cells, both microbial and metazoan, and is central to the development of multicellularity. Microbes in a ‘free-living’ environment attach to substrates, often in complex biofilms, to maintain themselves within a specific ecological niche. However, attachment is also central to parasitism and the trypanosome and Leishmania parasites are excellent systems to study attachment as they form both cell:cell and cell:substrate transmembrane attachment structures. They have a cell:cell junctional structure called the Flagellum Attachment Zone (FAZ) that connects the flagellum to the cell body. This structure is crucial for defining cell shape and form; we have defined its architecture and using innovative proteomic approaches, we discovered 8 proteins in the FAZ and showed that FAZ is assembled at a spatially distinct site to that of the flagellum. In addition, these parasites utilise their flagella to attach to substrates in their insect vectors, where they form an attachment plaque - a cell:substrate transmembrane attachment structure. Recently, we have begun to investigate the architecture and assembly of the attachment plaque in trypanosomes and Leishmania.
- How is the assembly of architecturally complex structures outside of the cell co-ordinated?
- How are existing structures such as a motile flagellum repurposed for attachment functions?
Alves AA et al., (2020) Control of assembly of extra-axonemal structures: the paraflagellar rod of trypanosomes. J Cell Sci. 133(10):jcs242271.
Sunter JD et al., (2015) Flagellum attachment zone protein modulation and regulation of cell shape in Trypanosoma brucei life cycle transitions. J Cell Sci. 128, 3117-3130. PMC4541047.
ii) Architecture of host-parasite interfaces
The flagellar pocket, present in microbes to mammalian cells, is a specialised region of the cell membrane at the base of the cilium/flagellum. In the trypanosome and Leishmania parasites it is the only site of endocytosis and exocytosis as well as the site of component sorting for flagellum construction. In concert with collaborators, we defined the detailed 3D structure of the Leishmania flagellar pocket and showed that it is remodelled during the life cycle, demonstrating that flagellar pocket architecture responds to changes in the extracellular environment and its functional requirements. In Leishmania we have shown that deletion of a single FAZ protein, FAZ5, alters flagellar pocket architecture and has a dramatic impact on parasite survival in vivo, illustrating the importance of understanding how cellular architecture is designed for pathogenicity. We have continued this work by undertaking a systematic screen of the role of FAZ proteins in flagellar pocket morphogenesis and function in Leishmania.
- How does flagellar pocket architecture contribute to its endocytic and associated functions?
- How does flagellar pocket architecture influence infectivity in the host/vector?
Halliday C et al., (2020) Role for the flagellum attachment zone in Leishmania anterior cell tip morphogenesis. PLoS Pathog. 16(10):e1008494.
Sunter JD et al., (2019) Leishmania flagellum attachment zone is critical for flagellar pocket shape, development in the sand fly, and pathogenicity in the host. Proc Natl Acad Sci U S A. 116:6351-6360.
We have strong links with research groups in Africa, primarily at the University of Ghana and we are combining our expertise to understand in detail the impact of animal African trypanosomiasis and develop new approaches to combat it.
My group regularly engages the public primarily through the Brookes Science Bazaar where we demonstrate how we can use microscopy to investigate the fascinating biology of parasites.