Heat shock signalling and response in African trypanosomes

Lead Research Organisation: Lancaster University
Department Name: Division of Biomedical and Life Sciences


The core body temperature of mammals is tightly regulated, and although increased temperatures can be fatal, periods of fever can used as part of a strategy to prevent infections by killing temperature sensitive bacteria and viruses. The African trypanosomes are parasites that are transmitted by the bite of an infected tsetse fly in sub-Saharan Africa, and cause disease in farm animals and humans which results in periods of fever. The parasite is able to survive these during period of fever by making specific proteins that help it cope with the elevated temperature it experiences. The way in which the parasite is able to do this is not clear, but we do know that it is different to the way mammals respond to elevated temperatures.

This project will investigate the way in which the parasite is able to sense and respond to elevated temperatures using a combination of experimental techniques to study parasite cells grown in flasks. We will examine the types of proteins the parasites produces to allow it cope with elevated temperatures, and how this response is co-ordinated. Studying this response is important as it will help us to understand how the parasite adapts to periods of fever in their hosts, knowledge that will help in the fight against the diseases they cause in farm animals and humans. Improved fundamental understanding of these molecular mechanisms is also important for our understanding of metabolic diseases and cancers where dysregulation occurs.

Technical Summary

The African trypanosomes Trypanosoma brucei and Trypanosoma congolense are vector borne parasites of domestic cattle and are a major cause of economic hardship in sub-Saharan Africa, with two sub-species of T. brucei also causing fatal infections in humans. Their ability to sense and respond to their host environment is critical for their survival and virulence, and is achieved despite a near complete lack of transcriptional control that results in a reliance on RNA binding proteins (RBPs).

Symptoms of human and animal African trypanosomiasis include periods of fever as high as 41 0C, eliciting a heat shock (HS) response in the parasites. Eukaryotic cells respond to HS by triggering a general arrest in protein translation and increasing HS protein (HSP) expression to aid protein folding and degradation. The eukaryotic HS response appears to be conserved in trypanosomes, but the mechanisms mediating the response are divergent.

In mammals HS translation arrest is triggered by the phosphorylation of eIF2alpha which blocks translation initiation, and up-regulation of HSP expression is regulated at the level of transcription. In T. brucei HS translational arrest is eIF2alpha-independent, and the zinc finger protein ZC3H11 binds to and stabilises HS responsive mRNAs to up-regulate HSPs expression. We have shown that in T. brucei HS alters the phosphorylation state of ZC3H11 and other RBPs that may play a role in translational arrest, P-body formation and upregulation of HSPs.

In this project we will used quantitative proteomics to measure the temporal changes in protein and phosphorylation state abundance that occur in T. brucei and T. congolense during HS and recovery. The functional role of phosphorylation sites on ZC3H11 and other candidate proteins will be determined, and the extent of conservation of HS sensing and response in T. congolense will be examined.


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Urbaniak MD (2023) A transferrin receptor's guide to African trypanosomes. in Cell surface (Amsterdam, Netherlands)

Description Symposium on African Livestock Trypanosomiasis, Tanzania (SALT-Tz) - Towards improving sustainable control of animal trypanosomiasis
Geographic Reach Africa 
Policy Influence Type Participation in a guidance/advisory committee
Impact Animal African Trypanosomiasis (AAT) is a major constraint on livestock health in sub-Saharan Africa, estimated by the Food and Agriculture Organization of the United Nations (FAO) to cost $1.5bn USD in lost revenue per year in sub-Saharan Africa. With no vaccine, trypanocidal drugs are the mainstay of control and there is an urgent need, and a timely opportunity, to better link stakeholders and decision-makers in AAT control with recent research progress. The meeting focused on AAT control, bringing researchers active in AAT research together with relevant stakeholders from AAT-affected countries, pharmaceutical companies and funders, to stimulate discussions and collaborations, and work towards identifying how to optimally deploy new innovations. The meetings primary focus was to bringing researchers and AAT stakeholders together to discuss sustainable control of AAT, with a spotlight on trypanocidal drug use, drug development, and issues influencing sustainable drug use, including drug resistance. Meeting Outcomes: 1. Informed guidelines on trypanocide use and resistance in the FAO progressive control pathway (PCP) for AAT in Tanzania. 2. Guided development of international guidelines to promote sustainable usage of trypanocides. 3. Stimulated collaborations between laboratory and operational research with disease control in the field, and between laboratory researchers (particularly North-South collaborations) Focus countries were Tanzania, Malawi and Ghana, but additional AAT endemic countries (Burkina Faso, Camaroon, Kenya, Rwanda, Mozambique, Nigeria, South Africa, Uganda) were represented and issues of regional and continental relevance were addressed.
URL https://www.fao.org/paat/news-and-events/news/detail-events/en/c/1620473/
Description Parasites in a Box outreach project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We have designed and created a 'Parasites in a Box' resource that contains interactive material and hands-on experiments about neglected tropical diseases, the insects that transmit them and the symptoms the parasites cause. The resource is used at public outreach events, events targeting schools and is regularly loaned to local schools, and highlights our research on a family of parasites known as trypanosomes. Feedback from participants (pupils and teachers) has reported increased interest in sciences and change in opinion towards neglected tropical diseases.
Year(s) Of Engagement Activity 2021,2022,2023