Integrative Biology of Emerging Infectious Diseases (IBEID) / Principal investigators
Trypanosome Cell Biology Unit
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
Research area of the Unit
Trypanosoma brucei is a flagellated parasite responsible for sleeping sickness in Central Africa. The parasite is transmitted by the bite of the tsetse fly. During their life cycle, trypanosomes have to adapt to changing environments (mammalian bloodstream, insect gut and salivary glands). Trypanosomes also represent exciting model organisms as they exhibit unique cellular features and are amenable to modern reverse genetics technology. Our group is interested in (1) flagellum formation and function and (2) the dynamics of trypanosome infections in vivo.
We demonstrated that the flagellum is critical for the trypanosome cell cycle and that it is constructed via a specific process called intraflagellar transport (IFT). We have visualised IFT for the first time in trypanosomes and have quantified IFT rates and revealed the dynamics of IFT proteins. We have identified a novel step in trypanosome development taking place in the salivary glands, showing that trypanosomes use a mixture of symmetric and asymmetric divisions to colonise the epithelium and to continuously produce infective parasites in the saliva.
Contribution to the programme
Despite WHO efforts, sleeping sickness is re-emerging in numerous rural areas of Central Africa. There is currently no vaccine and the few available drugs provoke severe side effects and are facing increasing problems of resistance. Since the almost exclusive mode of infection is via the bite of the tsetse fly, we will examine the early steps of trypanosome infection using live imaging. Flies will be infected with fluorescent trypanosomes and in vivo imaging will reveal how parasites behave in the skin, how do they differentiate and how do they migrate to reach the blood, a complete back box (collaboration with the unit of P. Bousso, Immunology Department). Adaptation to the various environments implies key sensing and migration events, some of which could be mediated by the flagellum. We have purified produced an exhaustive proteomic analysis of intact flagella and identified multiple candidate molecules. We will monitor their role and dynamics during the early steps of infection in the mouse model. Importantly, these experiments will be carried out upon the bite of a tsetse fly and not after syringe injection.
References over the past 5 years
1. Absalon, S., Blisnick, T., Bonhivers, M., Kohl, L., Cayet, N., Toutirais, G., Buisson, J., Robinson, D., and Bastin, P. (2008). Flagellum elongation is required for correct structure, orientation and function of the flagellar pocket in Trypanosoma brucei. J Cell Sci 121, 3704-3716 (Front cover).
2. Absalon, S., Blisnick, T., Kohl, L., Toutirais, G., Dore, G., Julkowska, D., Tavenet, A., and Bastin, P. (2008). Intraflagellar transport and functional analysis of genes required for flagellum formation in trypanosomes. Mol Biol Cell 19, 929-944 (cited on F1000).
3. Demonchy R, Blisnick T, Deprez C, Toutirais G, Loussert C, Marande W, Grellier P, Bastin P, Kohl L. (2009) Kinesin 9 family members perform separate functions in the trypanosome flagellum. J Cell Biol 187, 615-622.
4. Rotureau, B., Subota, I., and Bastin, P. (2011). Molecular bases of cytoskeleton plasticity during the Trypanosoma brucei parasite cycle. Cell Microbiol 13, 705-716.
5. Subota, I., Rotureau, B., Blisnick, T., Ngwabyt, S., Durand-Dubief, M., Engstler, M., and Bastin, P. (2011). ALBA proteins are stage regulated during trypanosome development in the tsetse fly and participate in differentiation. Mol Biol Cell 22, 4205-4219.
6. DuBois, K.N., Alsford, S., Holden, J.M., Buisson, J., Swiderski, M., Bart, J.M., Ratushny, A., Wan, Y., Bastin, P., Barry, J.D., et al. (2012). NUP-1 is a large coiled-coil nucleoskeletal protein in trypanosomes with lamina-like functions. PLoS Biology, 10 e1001287.
7. Rotureau, B., Subota, I., Buisson, J., and Bastin, P. (2012). A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly. Development 139, 1842-1850.