Maryse Lebrun, Inserm Research Director based in Montpellier, is studying parasites as infamous as Toxoplasma gondii and Plasmodium falciparum, the agents of toxoplasmosis and malaria. Her objective? Describe the mechanisms of interaction of these organisms with the host cells they infect. Indeed, the processes involved differ markedly from those used by bacteria and which have been described to date. With her work involving the discovery of novel biological mechanisms and potential new avenues in treating these diseases, her recent achievement of a 2.5-million-euro European Research Council (ERC) Advanced Grant should come as no surprise.
The story is of a career devoted to thwarting parasites which insidiously penetrate the cells of their hosts – often humans – causing such severe diseases as malaria and toxoplasmosis. This was not necessarily what Lebrun had in mind when she embarked on her cellular biology degree in Nantes, or even her microbiology post-graduate diploma (DEA) in Rennes. It all clicked into place during her Ph.D. in 1990 when she joined an Inra laboratory, in Tours, which was studying animal diseases – particularly those of bacterial origin. She was particularly interested in Listeria monocytogenes, leading her to reach out to Pascale Cossart at Institut Pasteur. An encounter that was to prove decisive for her career. "This leading figure in French microbiology really gave me a taste for bacteriology and microbiology in general, as well as the desire to study host/pathogen interactions and invasion phenomena", explains Lebrun. She joined Cossart’s laboratory and it was following another postdoc in Daniel Bout’s laboratory in Tours that she began to specialize in parasites, particularly Toxoplasma.
Her new knowledge led to her recruitment by Inserm in 2002 as staff scientist in the Plasmodium and Toxoplasma: Membrane Biogenesis and Host Cell-Parasite Interactions research unit (JRU5235) in Montpellier. There she continued her research into Toxoplasma gondii. "It was a promising area because while many teams had worked on bacterial invasions, very few had done so on parasites: almost everything remains to be discovered", explains Lebrun. This won her several grants, including from the French National Research Agency (ANR), enabling her to discover a novel invasion mechanism hitherto never described for parasites, in which they produce both the lock and key used to enter the host cells. The researcher also described other molecules of attachment, invasion and virulence contained in the intracellular compartments of these parasites: micronemes and rhoptries. In the meantime, promoted to Research Director in 2009 in the same unit in Montpellier, Lebrun became renowned in the community of experts in Toxoplasma and Plasmodium, a parasite which works in a very similar way when it comes to cell invasion.
In the quest for totally new mechanisms!
But although she now had the contents of the intracellular compartments of the parasites quite well figured out, Lebrun and the scientific community in general had no knowledge of the various circumstances and how these molecules necessary for infection are released, particularly at rhoptry level. Hence her application to the ERC, for new funding in order to clarify these points. The institution was immediately interested because "while we know practically nothing about these mechanisms of secretion, we know enough to say that they have nothing in common with those deployed by the bacteria to inject their virulence factors into the host cell. This means that we are embarking on research into totally new mechanisms", she clarifies. This project therefore has two merits: discover novel biological pathways and – maybe – open up new avenues in the treatment of toxoplasmosis and malaria. A dual objective that won over the ERC, which has awarded her a grant of 2.5 million euros for five years, starting from July 2020.
She will be able to grow her team, which currently counts ten people, and launch new investigations. One engineer and three postdocs are already in the pipeline for the development of a paramecium ciliate model, whose cell compartments present similarities with the rhoptries, in order to understand how the virulence factors pass through the host cell membrane, or to study the expression of the pathogenic potential of the parasites – which will now have everything to fear!
Maryse Lebrun leads the Host-Cell Invasion and Intracellular Survival of Apicomplexa Parasites team within the Plasmodium and Toxoplasma: Membrane Biogenesis and Host Cell-Parasite Interactions research unit (JRU 5235 CNRS/Université Montpellier), in Montpellier.