Jobs and PhDs
(MRC DTP) GlycoTryps: Investigating The Role of the Glycocalyx in mediating host-pathogen interactions and tissue immunity, University of Manchester
African trypanosomes are the causative agents of devastating diseases of medical and veterinary importance, including sleeping sickness in humans and extreme wasting disease in animals in Sub-Saharan Africa. Conservative estimates suggest that over 20 million people are currently at risk of infection. Furthermore, this infection also has a massive economic impact on agriculture leading to the loss of ~ 20 billion dollars per year in cattle stock. Our recent work has shown that localised immune responses are essential to drive the various arms of the pathology in both mice and humans, but the mechanisms that kickstart these processes are not understood.
In order to induce such devastating effects on the host, African trypanosomes first need to overcome the critical barrier imposed by the vasculature, which is characterised by having a rich and dense surface glycocalyx. The endothelial surface glycocalyx is an understudied structure composed of glycoproteins (primarily proteoglycans) and glycolipids, and is present on a range of cells including the endothelium and macrophages. We hypothesise that the interaction between African trypanosomes with the endothelial glycocalyx has profound implications for tissue immunity and pathology. In this context, the endothelial glycocalyx becomes the ultimate physical site dictating host-pathogen interactions and downstream tissue responses.
Progress in understanding the glycocalyx function in biology has been hampered by the lack of established techniques to study it experimentally. This project will determine for the first time the role of the endothelial and leukocyte glycocalyx in the local immune responses against African trypanosomes in tissues critical for disease transmission (skin, adipose tissue) and pathology (brain and brain borders) by establishing a range of cutting edge techniques.
We will analyse and compare the glycocalyx across tissue sites and time points of infection using multiplex imaging to understand the spatial distribution of African trypanosomes in relation to points of leukocyte extravasation and tissue entry. We will also determine the mechanisms that mediate trypanosome-glycocalyx interaction using cutting-edge 3-dimensional tissue imaging (e.g., lightsheet microscopy, electron tomography) and genome-wide screening to define the nature of the niches formed between parasites and glycocalyx niches, as well as to identify parasite-specific components essential for such processes. By manipulating the glycocalyx of immune and endothelial cells in various models of infection, we will demonstrate for the first time the functional relevance of the glycocalyx in mediating host-pathogen interactions, providing unparalleled insights into how these important aspects dictate tissue responses to infection.
https://research.manchester.ac.uk/en/persons/juan-quintana
https://research.manchester.ac.uk/en/persons/matthew-sinton
https://research.manchester.ac.uk/en/persons/douglas.dyer
Eligibility
Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form you must select MRC DTP PhD Programme. If you select the incorrect programme your application cannot be considered. Full details on how to apply can be found on the MRC DTP website.
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application, please contact our admissions team.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website.
Studentship funding is for 4 years and covers tuition fees and an annual stipend. This does not include any costs associated with relocation.
Postdoc, Trypanosome Transmission Group - Trypanosome Cell Biology Unit, Pasteur Institute
A 24-month post-doctoral position starting on March 1st 2025 and funded by the French National Research Agency (ANR) is available in the Trypanosome Cell Biology Unit at Institut Pasteur in Paris (Trypanosome Transmission Group: https://research.pasteur.fr/en/team/groupbrice-rotureau/).
Project: TrypaDiff - Glycerol, a new key player in the trypanosome parasite cycle Trypanosoma brucei is an extracellular parasite responsible for sleeping sickness in Africa and transmitted by a blood-feeding insect vector, the tsetse fly. In its mammalian host, the rapidly dividing slender forms predominate in the blood and tissues. At the peak of parasitaemia, slender forms differentiate into growth-arrested stumpy forms (ST) to protect the host by preventing high parasitaemia. Slender to stumpy differentiation relies on a quorum sensing mechanism triggered by the accumulation of di- and tripeptides produced by oligopeptidases excreted by the parasites. The current model of T. brucei transmission from mammals to the insect vector emphasises the key role of the quorum sensing-derived stumpy forms (ST-QS) produced in the blood. However, this may not be the only differentiation pathway. Our recent unpublished data showed that glycerol, which is abundant in the skin and adipose tissues where the parasites also reside, induces differentiation of slender to stumpy-like forms (ST-Glyc), which are competent for differentiation into parasitic forms present in the insect. We thus propose a rational working hypothesis, in which the glycerol present in the skin would induce the production of ST-Glyc mostly responsible for the parasite transmission to the fly. To study this new paradigm, our ANR-funded consortium composed of Dr. Brice Rotureau (IPP), Dr. Lucy Glover (IPP) and Dr. Frédéric Bringaud (Bordeaux, coordinator of the TrypaDiff project) will (i) characterize glycerol-induced stumpy-like forms, (ii) determine the biological relevance of these parasites, and (iii) characterize the signaling pathway(s) involved in their glycerol-induced differentiation. This program will contribute to a better understanding of the developmental biology of trypanosomes responsible for human and domestic animal diseases and will highlight possible new ways to control parasite transmission.
Experimental approaches: CRISPR-cas9 genetic engineering, microfluidic organoid model, experimental infections in mice and flies, in vivo imaging.
Requirements: Candidates with a recent PhD in Biological Science, especially in Parasitology or Cell Biology are encouraged to postulate. Experience in experimental infection in mice is required. Highly motivated and autonomous candidates are wanted. Skills in entomology or in vivo imaging or microfluidic models would be greatly appreciated.
Application: Applicants should send a CV, a bibliography, a motivation letter and the names of three references in a single pdf file to Dr. Brice Rotureau (rotureau@pasteur.fr) before November 30th 2024.
Position Title: Postdoctoral Researcher Location: Montpellier France
