Installé dans l’appartement où Louis Pasteur passa les sept dernières années de sa vie, le musée Pasteur constitue une occasion unique de pénétrer dans l’univers de l’illustre savant : de visualiser sa vie au quotidien aux côtés de son épouse et de traverser son œuvre scientifique abondante.
Faire un don à l’Institut Pasteur, c’est contribuer aux avancées de ses recherches biomédicales et être ainsi associé à ses chercheurs et à leurs découvertes sur les cancers, les maladies du cerveau, les maladies infectieuses, et bien d’autres encore…
La stratégie scientifique de l’Institut Pasteur s’appuie sur le développement de thématiques originales et innovantes, encourageant les échanges et la pluridisciplinarité des approches de recherche. Pour relever ce défi, l’Institut Pasteur met à la disposition de ses équipes les ressources technologiques indispensables à leur réactivité et à une recherche de haut niveau.
Le Centre médical de l’Institut Pasteur est un centre de santé conventionné secteur 1. Il propose une offre de soin à destination des voyageurs, et la prise en charge diagnostique et thérapeutique des maladies infectieuses, tropicales et allergiques. Le Centre médical de l’Institut Pasteur, engagé depuis 2008 dans la mise en place d’une démarche Qualité, est le premier centre de santé français à recevoir en janvier 2011 la certification qualité "AFAQ Centre de santé" de l'AFNOR Certification.
Depuis la création du premier cours de « microbie technique » en 1889, l’enseignement reste une priorité pour l’Institut Pasteur. Reconnu au niveau international, la qualité de l’enseignement de l’Institut Pasteur lui permet d’accueillir chaque année des étudiants venus du monde entier pour parfaire leur formation ou compléter leur cursus.
Doctoral school affiliation: CDV - Compléxité du Vivant
Presentation of the laboratory and its research topics:
The laboratory’s primary goal is to identify molecules, which are both implicated in parasite evasion of the host’s immune system and could ultimately be used as targets in the development of new therapies. The team has been studying experimental models of human Chagas disease and animal trypanosomosis, two of the “most neglected diseases” that afflict the poor and powerless in developing regions of sub-Saharan Africa, Asia and the Americas. Chagas’ disease, the third largest disease burden in Latin America, is caused by Trypanosoma cruzi. It affects at least 10 million people and 100 million people are at risk. Animal trypanosomosis (Nagana) is a major livestock challenge, which is mainly caused by Trypanosoma vivax, causes about 3 million cattle deaths annually, has a severe impact on African’s agriculture, and was recently introduced into South America and Mauritius. The team has recently drawn its attention to other protozoan parasites of the trypanosomatid family which are equally considered as “neglected”: Leishmania donovani and L. major, responsible respectively for visceral and cutaneous Leishmaniasis to study the infectious process of these diseases that threaten about 350 million people in 98 countries or territories around the world, most particularly in Asia, Eastern and Northern Africa and the Mediterranean and Amazonian bassins. No vaccines have yet been developed against all these infections. The pathogenesis differs among those trypanosomatid infectious processes, reflecting the different interactions of these parasites with their hosts, but important immunological dysfunctions are involved in the development of these seriously disabling illnesses.
Description of the project:
Trypanosoma vivax is a parasite in the genus Trypanosoma. It causes the disease Nagana, also known as animal trypanosomosis, affecting cattle or wild mammals. It is mainly occurring in West Africa (transmitted by tsetse fly), although it has spread to South America (transmitted by tabanids). Trypanosoma vivax is one of the most common parasites responsible for animal trypanosomosis but so far very few studies have been conducted on the parasite’s biology. This is in part due to the fact that no reproducible experimental methods had been developed so far to maintain the different evolutive forms of this trypanosome under laboratory conditions. We have developed murine infection models and axenic cultures that have enabled the genetic manipulation of this parasite and the obtention of stably transfected mutants that continue metacyclogenesis and are infectious in immunocompetent rodents. In particular, a luciferase-expressing strain has been used to follow parasite dynamics in vivo in real time (see references here below).
African trypanosomes parasites undergo complex morphological changes as they move between insect and mammal over the course of their life cycle. In particular, they use antigenic variation of a surface protein named the variant surface glycoprotein (VSG) to escape from immune system of the host. In T.brucei (the causative agent of human sleeping sickness) this phenomenon has been extensively studied. In T.vivax, studies of the animal infectious process and early immune responses suggest that antigenic variation is less effective than the one observed in T. brucei, suggesting that other proteins can be involved in immune system evasion of the parasite. Interestingly, some sets of proteins are absent in other African trypanosomes and present in both T. cruzi and T.vivax, these include a Proline Racemase and MASP (mucin-associated surface protein). These two proteins have been described as important for parasite development and host immune system regulation and/or activation.
The principal goal of the project is to understand parasite/host relationship and investigate specific expression of key parasite moieties at the different stage of development. Recently, we have started transcriptome and proteomic approaches (in collaboration with the Sanger Institut and Liverpool University) to compare expression profiles of the 3 forms of T. vivax (epimastigotes (the insect replicative from), trypomastigote metacyclics (the infectious form), and the mammalian Blood Stream replicative form (BSF).
The project will be essentially centered on three tasks :
Task 1: The lab has open the way for the genetic manipulation of T. vivax. You will participate to the creation of new tools to study this parasite and gene function. In particular, you will be in charge of developing an effective RNA interference system in T. vivax, based on strategies previously developed for T. brucei, which have proven their efficiency. Preliminary results indicate that the RNAi machinery is functional in T. vivax since basic elements like Argonaute and Dicer are present in its genome. This part of the project includes plasmid and T.vivax strains constructions. The validations of RNAi in T.vivax will be performed using classical knock down approaches of the tubulin gene.
Task 2: Genes identified as stage specific by the “omics” analyses will be further characterized, and their role in parasite escape and persistence in the host will be evaluated. First, you will confirm the expression and localization of these stage-specific proteins using conventional techniques: qPCR, fusion protein, immunofluorescence. In addition using recombinant proteins expressed in E.coli, including VSG, MASP, you will analyze the humoral responses of mice during the course of infection. In the case of MASP, comparative studies between T. vivax and T. cruzi can be envisaged since both animal models are mastered in the lab.
Task 3: You will construct T. vivaxknock down strains using the RNAi system you will have developed for genes identified in Task 2. The dynamic of infection for these recombinant strains will be monitored in murine models, using real time bio-imaging techniques that have been already set up in the lab, by the use of genetically modified parasites, single or double expressors of luciferase and immunofluorescence reporter genes.
D'Archivio S., Cosson A., Medina M., Lang T., Minoprio P., Goyard S. (2013)
Non-Invasive In Vivo Study of The Trypanosoma Infectious Process Consolidates the Brain Commitment in Late Infections. PlosNTD 7,e1976, 1-9.2.
D’Archivio, S., Medina, M., Cosson, A., Chamond, N., Rotureau, B.,Minoprio, P., Goyard, S. (2011). Genetic engineering of Trypanosoma (Dutonella) vivax and in vitro differentiation under defined axenic conditions. PlosNTD 5, e1461, 1-12.
Blom-Potar, M.C., et al., Trypanosoma vivax infections: pushing ahead with mouse models for the study of Nagana. II. Immunobiological dysfunctions. PLoS Negl Trop Dis, 2010. 4(8).
Chamond N, Cosson A, Blom-Potar MC, Jouvion G, D'Archivio S, Medina, M., Droin-Bergère, S., Huerre, M. Goyard,S., Minoprio, P. (2010).Trypanosoma vivax infections : Pushing ahead with mouse models for the study of Nagana.I. Parasitological, Hematological and Pathological Parameters. PlosNTD, 4, e792, 1-10.
De Pablos, L.M. and A. Osuna, Multigene families in Trypanosoma cruzi and their role in infectivity. Infect Immun, 2012. 80(7): p. 2258-64.
Jackson, A.P., et al., A cell-surface phylome for African trypanosomes. PLoS Negl Trop Dis, 2013. 7(3): p. e2121.
Trypanosoma vivax, in vivo imaging, Nagana, Neglected disease, RNA interference
Expected profile of the candidate (optional):
The candidate should have a scientific background in parasitology, microbiology or immunology and some hands-on experience and skills in molecular biology is recommended. Initiative and responsibility will be appreciated in addition to a strong team spirit.