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Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for disease

Periodic Reporting for period 3 - FatTryp (Exploring the hidden life of African trypanosomes: parasite fat tropism and implications for disease)

Période du rapport: 2021-08-01 au 2023-01-31

We have recently discovered that the adipose tissue (fat) is a major reservoir for the extracellular protozoan Trypanosoma brucei and that, within this environment, parasites become phenotypically different from those in the blood. Our study exposed novel biology of the T. brucei life cycle, yet it remains unknown how parasites adapt to the fat and how parasite fat tropism affects disease. Our first aim is to determine the molecular and cellular mechanisms underlying T. brucei fat tropism. We will perform a genetic screen in mice to identify key parasite genes required for establishing and maintaining chronic infection in the fat. Together with the information of the transcriptome and proteome, we will identify the mechanistic steps underlying parasite tissue-adaptation. Our second aim is to identify the consequences of T. brucei fat tropism for the host and the importance for disease. We will first investigate if parasites can egress from the fat. We will also determine if parasites induce lipid breakdown in the host, leading to loss of fat mass. Finally, we will measure the impact of fat tropism in general traits of disease, including host survival and transmission potential.

This project represents a completely novel research avenue built on recent work from my laboratory. By uncovering fundamental aspects of the biology of T. brucei, we will also improve the understanding of clinically relevant features of African trypanosomiasis, including relapses and weight loss. In addition, since parasite fat tropism has also been observed in malaria and Chagas’ disease, our findings will help elucidate disease mechanisms relevant to other infectious diseases.
Aim 1. Determine the molecular and cellular mechanisms behind parasite fat tropism
Using a combination of mathematical modelling and cellular tools, we discovered that in the adipose tissue trypanosomes become persister-like cells: they replicate more slowly, synthesize proteins at a lower rate and switch their metabolism. In parallel, we demonstrate that Fine Needle Aspiration may be a useful tool to diagnose trypanosomiasis, especially when parasitemia in the blood is undetectable.
Aim 2. Determine the consequences of parasite fat tropism for host and disease
We have investigated how parasites distribute in the vasculature and we showed that parasite extravasation is an active process. Interactions with endothelial receptors appear to be necessary for tissue tropism.
Trypanosomiasis is associated to emaciation. We found that a T. brucei infection activates lipolysis of triglycerides in adipose tissue. Genetic ablation of this pathway prevents loss of fat mass, but results in an accelerated loss of lean mass and increased disease severity.
All results described in section above are novel and go beyond the state of the art. Till the end of the project, we expect:
1. To show the metabolic adaptations of parasites to adipose tissue and consequences of this adaptation to parasite virulence.
2. To identify the parasite genes involved in tissue tropism
3. The mechanism by which parasites interact with vasculature and cross from blood into tissues.
Graphical abstract
Trypanosomes inside a vessel in the brain