How do African trypanosomes invade host tissues?
Lead Research Organisation:
University of York
Department Name: Biology
Abstract
How do African trypanosomes invade host tissues?
African trypanosomiasis is characterised by initial waves of parasitaemia in the bloodstream, followed by invasion of the central nervous system. Recent studies highlighted the importance of tissues and organs as a potential reservoir and protective environment for the creation of the characteristic waves of parasitaemia, drug resistance and parasite transmission (Trindade et al., 2016; Beaver et al., 2022). However, little is known about the dynamic flux between tissues, their roles for the bloodstream re-invasion and their influence on the parasites' life cycle (Cayla et al., 2019).
Recent studies have identified an unconventional secretory autophagy-related pathway, called lysosome exocytosis, that has been implicated in secretion peptidases/hydrolases enabling host cell invasion by the worm C. elegans (Naegeli et al., 2017). The aim of the project is to understand how peptidase secretion through lysosome exocytosis enables parasite development and host tissue invasion of the T. brucei. This research will provide an understanding of the parasite's life cycle and disease progression where compartments may play a role. This will require the use of a range of cutting-edge techniques such as longitudinal in vivo infection, CRISPR/Cas9 gene editing, quantitative proteomics, proximity-labelling, enzymatic assays and both in vivo/vitro imaging. The PhD student will gain expertise in trypanosome biology, cell-signalling regulation, proteomics, microscopy and host-pathogens interactions.
Impact:
The economic losses in cattle production dgue to African trypanosomiasis are in the range of US$1.0-1.2 billion, with about 3 million deaths and 35 million doses of trypanocidal drugs administered on cattle per year (Bekele, 2015). In humans, this disease is still considered as a neglected tropical disease. Therefore, this project investigating the molecular mechanisms responsible for the disease progression has a potential for translational development for much needed future screening/diagnosis (parasites "hiding" in organs) and combative strategies. In addition, the molecular mechanisms regulating lysosome exocytosis and its function remain a major mystery in eukaryote biology and this project will therefore provide critical understanding of how parasites persist and develop in vivo.
Working environment:
Our laboratories provide a supportive and collaborative environment in which the PhD student can expand their range and learn new techniques. The PhD student will also join a team of researchers in the York Biomedical Research Institute investigating cellular processes in parasites that cause African trypanosomiasis and leishmaniasis. The Department of Biology is renowned internationally for its research and strives to provide a working environment which allows all staff and students to contribute fully, flourish, and excel.
Objectives:
1) Investigating the release of peptidases by the lysosome exocytosis pathway.
2) Revealing the role of peptidases for host tissue invasion in the mammalian host.
3) Shedding light on the function of mammal organs for the dynamic of the parasite infection and development.
Novelty:
This research will provide understanding of parasite's life cycle and disease progression regulated by lysosome exocytosis and peptidase secretion. It will build an atlas of parasite protein expression within the different tissues and reveal their function for the disease progression and transmission.
African trypanosomiasis is characterised by initial waves of parasitaemia in the bloodstream, followed by invasion of the central nervous system. Recent studies highlighted the importance of tissues and organs as a potential reservoir and protective environment for the creation of the characteristic waves of parasitaemia, drug resistance and parasite transmission (Trindade et al., 2016; Beaver et al., 2022). However, little is known about the dynamic flux between tissues, their roles for the bloodstream re-invasion and their influence on the parasites' life cycle (Cayla et al., 2019).
Recent studies have identified an unconventional secretory autophagy-related pathway, called lysosome exocytosis, that has been implicated in secretion peptidases/hydrolases enabling host cell invasion by the worm C. elegans (Naegeli et al., 2017). The aim of the project is to understand how peptidase secretion through lysosome exocytosis enables parasite development and host tissue invasion of the T. brucei. This research will provide an understanding of the parasite's life cycle and disease progression where compartments may play a role. This will require the use of a range of cutting-edge techniques such as longitudinal in vivo infection, CRISPR/Cas9 gene editing, quantitative proteomics, proximity-labelling, enzymatic assays and both in vivo/vitro imaging. The PhD student will gain expertise in trypanosome biology, cell-signalling regulation, proteomics, microscopy and host-pathogens interactions.
Impact:
The economic losses in cattle production dgue to African trypanosomiasis are in the range of US$1.0-1.2 billion, with about 3 million deaths and 35 million doses of trypanocidal drugs administered on cattle per year (Bekele, 2015). In humans, this disease is still considered as a neglected tropical disease. Therefore, this project investigating the molecular mechanisms responsible for the disease progression has a potential for translational development for much needed future screening/diagnosis (parasites "hiding" in organs) and combative strategies. In addition, the molecular mechanisms regulating lysosome exocytosis and its function remain a major mystery in eukaryote biology and this project will therefore provide critical understanding of how parasites persist and develop in vivo.
Working environment:
Our laboratories provide a supportive and collaborative environment in which the PhD student can expand their range and learn new techniques. The PhD student will also join a team of researchers in the York Biomedical Research Institute investigating cellular processes in parasites that cause African trypanosomiasis and leishmaniasis. The Department of Biology is renowned internationally for its research and strives to provide a working environment which allows all staff and students to contribute fully, flourish, and excel.
Objectives:
1) Investigating the release of peptidases by the lysosome exocytosis pathway.
2) Revealing the role of peptidases for host tissue invasion in the mammalian host.
3) Shedding light on the function of mammal organs for the dynamic of the parasite infection and development.
Novelty:
This research will provide understanding of parasite's life cycle and disease progression regulated by lysosome exocytosis and peptidase secretion. It will build an atlas of parasite protein expression within the different tissues and reveal their function for the disease progression and transmission.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/W006944/1 | 01/10/2022 | 30/09/2028 | |||
| 2888919 | Studentship | MR/W006944/1 | 01/10/2023 | 30/09/2027 | NATHALIA Thompson |