Country: UK
Type: Ph.D. Project
Deadline: December 13, 2024
Details: https://www.dimen.org.uk/applications
About the Project
Leishmania parasites
are responsible for causing a collection of devastating diseases affecting
millions of people worldwide. They are spread via infected female sand flies,
who feed on blood to produce eggs. Inside the sand fly, Leishmania proliferate
and eventually differentiate into one of two forms. The metacyclic form
parasites are the motile, infectious cells that invade human macrophages and
the second, haptomonad form remains less well characterized. Haptomonad form
parasites attach to the sand fly stomodeal valve, maintaining infections after
a bloodmeal, and causing damage to the valve, which improves regurgitation
during a feed (Yanase et al. 2024, Serafim et al. 2018).
Interestingly, recent data shows that haptomonad form cells may also infect
macrophages and form a large part of the infectious dose (Catta-Preta et
al. 2024). This implicates haptomonad form Leishmania as an
important and understudied component of human infections. The cellular
signalling involved in commitment to becoming a haptomonad and mechanism of
attachment remains elusive. You will uncover how attached Leishmania contribute
to infection by addressing the following objectives:
•
Determine infectivity of haptomonad form Leishmania
•
Uncover the mechanism by which Leishmania establish an
attachment
•
Explore strategies to disrupt disease transmission
This
project will entail a range of cutting-edge technologies in genetic
manipulation, protein-protein interactions and cell signalling pathway
deconvolution. You will expand a barcoded knockout library for the development
and optimization of an attachment assay. Next generation sequencing will
produce results for quantitative analysis of barcode representation.
Protein-protein interactions will be explored by expression of Leishmania extracellular
domains as biotinylated proteins expressed in HEX cells. These will be
clustered around streptavidin to make tetramers to probe for attachment to PSG
and sand fly culture lines. Validation and characterization of outputs will
involve genetic manipulation, cell staining, flow cytometry and proteomic
methods.
Impact
and Novelty:
This
research will provide an improved understanding of the parasite life cycle,
specifically disease transmission. There are no vaccines or drugs which can
prevent infection. New transmission blocking strategies depend on a
comprehensive knowledge of parasite-insect interaction. The primary supervisor
has Leishmania mutants which can be used to produce cell
cultures containing an exceptionally high proportion of this life cycle stage
which is otherwise rare. These, along with proteomic and transcriptomic
datasets generated using them, provide a unique tool. Two novel methods will be
used for assessing attachment, a kinome-wide barcoded library (Baker et
al. 2021) and a Leishmania cell surface library (Roberts
et al. 2024).
Supervision
and support:
The
supervisory team combines expert knowledge in molecular parasitology and
host-parasite interactions through cellular signalling. The primary supervisor
is the recent recipient of a career development award and will provide much of
the practical training. During the project you will gain training in a variety
of both lab-based skills and computer-based analysis of data. Our laboratories
provide a supportive and collaborative environment in which a PhD student can
expand their range and learn new techniques.
Supervisor: Nicola
Baker
Second
supervisor: Prof. Gavin Wright
Benefits
of being in the DiMeN DTP:
This
project is part of the Discovery Medicine North Doctoral Training Partnership
(DiMeN DTP), a diverse community of PhD students across the North of England
researching the major health problems facing the world today. Our partner
institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield)
are internationally recognised as centres of research excellence and can offer
you access to state-of-the-art facilities to deliver high impact research.
We
are very proud of our student-centred ethos and committed to supporting you
throughout your PhD. As part of the DTP, we offer bespoke training in key
skills sought after in early career researchers, as well as opportunities to
broaden your career horizons in a range of non-academic sectors.
Being
funded by the MRC means you can access additional funding for research
placements, training opportunities or internships in science policy, science
communication and beyond.
References:
Yanase,
R., Pruzinova, K., Owino, B.O. et al. Discovery of essential
kinetoplastid-insect adhesion proteins and their function in Leishmania-sand
fly interactions. Nat Commun 15, 6960 (2024). https://doi.org/10.1038/s41467-024-51291-z
Serafim,
T.D., Coutinho-Abreu, I.V., Oliveira, F. et al. Sequential blood meals promote
Leishmania replication and reverse metacyclogenesis augmenting vector
infectivity. Nat Microbiol 3, 548–555 (2018). https://doi.org/10.1038/s41564-018-0125-7
Carolina
Catta-Preta, Kashinath Ghosh, David Sacks et al. Single-cell atlas of
Leishmania major development in the sandfly vector reveals the heterogeneity of
transmitted parasites and their role in infection, 18 March 2024, PREPRINT
(Version 1) available at Research Square. https://doi.org/10.21203/rs.3.rs-4022188/v1
Baker,
N., Catta-Preta, C.M.C., Neish, R. et al. Systematic functional analysis of
Leishmania protein kinases identifies regulators of differentiation or
survival. Nat Commun 12, 1244 (2021). https://doi.org/10.1038/s41467-021-21360-8
Roberts
AJ, Ong HB, Clare S, Brandt C, Harcourt K, Takele Y, Ghosh P, Toepp A, Waugh M,
Matano D, Färnert A, Adams E, Moreno J, Mbuchi M, Petersen C, Mondal D, Kropf
P, Wright GJ. A panel of recombinant Leishmania donovani cell surface and
secreted proteins identifies LdBPK_323600.1 as a serological marker of
symptomatic infection. mBio 15:e00859-24 (2024). https://doi.org/10.1128/mbio.00859-24
Funding
Notes
Studentships
are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will
cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also
aim to support the most outstanding applicants from outside the UK and are able
to offer a limited number of full studentships to international applicants.
Studentships
commence: 15 Sep 2025
Good
luck!
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