2020-12-02 / Congratulations to Chloé Morel who presented her poster at the SBM annual conference.
This presentation was zoom made and recorded!!
Mitochondrial dynamics in Trypanosoma brucei life cycle
Trypanosomes are parasites responsible for the African sleeping sickness as well as the related cattle disease Nagana. During the trypanosome life cycle, the parasite exist in at least two replicative forms; the procyclic form, transmitted by the tsetse fly Glossina spp., and the bloodstream form responsible for diseases in vertebrates. The pathogenic trypanosomes have a single mitochondrion, unlike most other eukaryotes that contain numerous. The shape and functional plasticity of their single mitochondrion undergoes spectacular changes, reflecting adaptation to different environments, alternating between the proline-rich haemolymph and tissue fluids of the blood-feeding tsetse fly and the glucose-rich blood of a mammalian host. The combination of these different states, among which the trypanosome mitochondrion oscillates, makes it an ideal model organelle for studying mitochondrial functional and dynamic transitions. Remodeling of the organelle suggests that trypanosomes possess fusion and fission machineries. We have identified putative components of these machineries, one of them is a putative mitofusin (TbMFN). TbMFN contains 21% of identity with the human MFN1, involved in mitochondria fusion, in addition of the dynamin characteristics domains, including the GTPase domain and the coiled-coil domain. Our main goal is to first characterize the putative TbMFN involved in mitochondrial dynamics and then to investigate the physiological relevance of mitochondrial fusion/fission machineries to the parasite’s life cycle.
2020-10 / iMet's project of the ParaFrap PhD Program
Project proposal for the attribution of a PhD grant within the ParaFrap PhD Program
Title of the project: Role(s) of glycerol metabolism in the biology of African trypanosomes
Main PI for the project: Frédéric BRINGAUD
Co-PI for the project: Brice ROTUREAU (Unit head: Philippe BASTIN)
KEYWORDS: trypanosome-adipocyte metabolic interactions; unusual glycerol-to-glucose preference; in vivo (fly and mouse) and in vitro approaches; production of trypanosome mutants; in vitro differentiation of parasites
Trypanosoma brucei, the agent of Human African Trypanosomiasis (HAT), undergoes a complex life cycle from the bloodstream of a mammalian host (BSF) to the alimentary tract (procyclic forms - PCF) and the salivary glands of its blood-feeding insect vector (the tsetse). BSF trypanosomes have been considered for decades to propagate exclusively in the fluids of its mammalian hosts and mainly in the blood. In a break with this dogma, the Co-PI of this project showed that most parasites actually reside in the extravascular compartment of the skin in the vicinity of hypodermal adipocytes (Capewell and Travaillé et al., eLife, 2016). In resonance with this major discovery, the PI of this project recently broke another strong dogma considering that T. brucei relies exclusively on the glucose provided by its mammalian hosts to feed its central carbon metabolism. Indeed, we established long-term conditions for growth of the parasite in glucose-free medium containing glycerol (Pineda et al., PLoS Pathog, 2018). Since adipocytes excrete large amounts of glycerol from lipolysis and glycolysis, we hypothesised that interactions between adipocytes and extravascular trypanosomes may confer a selective advantage to the parasites in the mammalian host.
In the glucose-free environment that is the midgut of the tsetse fly vector, PCF trypanosomes primarily use proline to feed their central carbon and energy metabolism. In these conditions, the parasite needs to produce glucose 6-phosphate through gluconeogenesis from metabolism of non-glycolytic carbon source(s). The PI and the Co-PI recently characterised the gluconeogenic pathway and showed that glycerol is an excellent gluconeogenic carbon source for PCF (Wargnies et al., PLoS Pathog, 2018). More interestingly, the PI showed that trypanosomes perform gluconeogenesis from glycerol even in the presence of glucose, making them the only known microorganism using gluconeogenesis in the presence of glucose. The new mechanism controlling this modulation of carbon source preference was elucidated and named "metabolic contest" (Allmann et al., BioRxiv, in revision in PLoS Biol). We hypothesised that this unique glycerol-to-glucose preference developed by PCF trypanosomes may have a crucial role for the growth and/or development of the parasite in its insect vector.
The objectives of this project are to understand the role(s) of glycerol metabolism during the entire development of Trypanosoma brucei (1) in the different organs of the insect vector (PCF and epimastigote trypanosomes), as well as (2) in the vascular and extravascular compartments of the mammalian host (BSF trypanosomes).
To address these questions, the PhD student will use a combination of in vivo (mice and tsetse flies) and in vitro approaches using wild-type and mutant (KO generated by CRISPR-Cas9 and/or RNAi) cell lines of the BSF and PCF trypanosomes. The in vitro approaches that will be used include the co-culture of BSF trypanosomes and adipocyctes, RBP6-driven differentiation of PCF into epimastigotes and metacyclics, production of trypanosome mutants, metabolomics, proteomics, etc.).
2020-06-04 / During the CoVid-19 lockdown the team kept contact but respecting the social distancing!!