Back to search form

Host-pathogen interaction : the influence of host tRNAs on the development of the malaria parasite

Research unit

UPR 9002 - Architecture et réactivité de l'ARN (IBMC)
15, rue Rene Descartes 67084 - Strasbourg Cedex

Group

Name: Aminoacylation des ARNt eucaryotes: contrôle et pathogénicité

Group leader: FRUGIER Magali - m.frugier@ibmc-cnrs.unistra.fr

Group leader's phone: 03 88 41 71 09

Website: Visit website

Group organization:
- Chercheurs: 2
- ITA: 2
- Doctorants: 2
- Post-Docs: 1
- Autres: 0

Publications of the team linked to the topic (3 last years):
1) Bour, T., Akaddar, A., Lorber, B., Blais, S., Balg, C., Candolfi, E., and Frugier, M., (2009) Plasmodial Aspartyl-tRNA Synthetases and Peculiarities in Plasmodium falciparum, J. Biol. Chem. 284, 18893–18903.
2) Jackson, K. E., Habib, S., Frugier, M., Hoen, R., Khan, S., Pham, J. S., Ribas de Pouplana, L., Royo, M., Santos, M. A. S., Sharma, A. and Ralph, S. A. (2011) Protein translation in Plasmodium parasites, Trends in parasitology, 27, 467-476.
3) Filisetti, D., Théobald-Dietrich, A., Mahmoudi, N., Rudinger-Thirion, J, Candolfi, E. and Frugier, M. (2013) Aminoacylation of Plasmodium falciparum tRNAAsn and insights in the synthesis of asparagine repeats. J. Biol. Chem, 288, 36361-36371.

About PhD

PhD Director: FRUGIER Magali - m.frugier@ibmc-cnrs.unistra.fr

Phone: 03 88 41 71 09

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Host-pathogen interaction : the influence of host tRNAs on the development of the malaria parasite

Project: 1. Introduction
Plasmodium falciparum is the most deadly of the five Plasmodium species that cause human malaria. Malaria is caused by red blood cells-infectious forms of Plasmodium parasites. However, the biology of sporozoites (the invading liver stage parasites) is poorly known. They are transmitted by Anopheles mosquitoes, invade rapidly the body, migrate to the liver, infect the hepatocytes and inside these cells transform to schizonts (clinically silent pre-erythrocytic life cycle stage).
Transfer RNAs (tRNAs) produced in Plasmodium and their putative involvement in regulatory networks are of particular interest. Indeed, several recent studies suggest that, outside their central role in translation, tRNAs do play a part in regulation mechanisms in several other eukaryotic parasitic organisms. For example, they have been shown to be involved in apoptosis, proliferation or RNA silencing regulations. Moreover cleavages of tRNAs that generate products with “micro-RNA-like” features have been detected in some eukaryotes (Aspergillus fumigatus and Trypanosoma cruzi) however their regulatory functions need to be confirmed.
Our recent data (to be published) show that host tRNAs are imported in sporozoites through a specific plasmodial receptor for tRNA, tRBP, and therefore increasing considerably the variability of tRNA sequences inside the parasite.
Based on all these observations, we propose to study the fate of both endogenous and imported host tRNAs in Plasmodium. Two hypotheses are predicted, (i) tRNAs participate only in Plasmodium translation and/or (ii) tRNA are involved in some unknown regulatory mechanisms in the parasite. Both propositions are not exclusive and imported host tRNAs could play a specific key role in the signaling pathway, which induces the switch from mosquito salivary gland sporozoites to infectious sporozoites capable of productive invasion of host hepatocytes. We will explore both hypothesis in our project.

2. Working packages

The pHD student will investigate:

1-the stage-dependent accumulation levels of endogenous tRNAs..
2- the expression pattern of Plasmodium tRNAs and the correlation with the evolution of its proteome (codon usage, already published by other teams) during the life cycle of the parasite.
Alternatively, the student will to study the host-parasite interaction and the role it plays in the parasite's pathogenicity. She/he will
3- design and produce a tRNA asparagine as an optimal substrate for the parasite asparaginyl-tRNA synthetase. Our goal will thus be to use the capacity of the parasite to import exogenous tRNAs to observe the effect of this particular tRNA on protein translation/expression in the sporozoite (sporozoite proteins are particularly rich in long asparagine stretches which role is still unknown).
4- develop this approach also in vivo. This will necessitate a collaboration with Eric Marois' team (IBMC) in order to design transgenic mosquitoes that express this tRNAAsn sequence and (i) see if it is indeed imported into the salavary gland sporozoites and (ii) study its effect on the development and the infectivity of the parasite.
3. Experimental approaches

-breeding and production of infectious mice and mosquitoes with P. falciparum (insectarium IBMC).
-Parasites purification (mosquito salivary glands and mouse blood)
-Purification of parasite RNAs and RNA Seq (sporozoites and blood stages stade)
-Molecular biology : construction and expression of tRNAs in vitro.

Wished skills: Knowledge of basic molecular biology, cellular biology and biochemistry
autonomous and dynamic person

Expertises which will be acquired during the training: -breeding and production of infectious mice and mosquitoes with P. falciparum (insectarium IBMC).
-Parasites purification (mosquito salivary glands and mouse blood)
-Purification of parasite RNAs and RNA Seq (sporozoites and blood stages stade) and proteomic
-Molecular biology : construction and expression of tRNAs in vitro.