Biomedical research institute
Biomedical research institute
Team Leader
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Catherine Lavazec |
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Achievement of malaria elimination requires development of novel strategies to interfere with parasite transmission. Plasmodium falciparum transmission stages develop in red blood cells that sequester in the bone marrow, and that appear only as mature stages in the peripheral blood. Our goal is to decipher the cellular mechanisms underlying sequestration of infected red blood cells in the bone marrow and their release into the bloodstream, and to establish that these mechanisms may be new targets to block malaria parasite transmission. |
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Contact : catherine.lavazec@inserm.fr - Tel : +33 1 40 51 64 37
Malaria remains a major global public health problem with half a million deaths annually. Achievement of malaria elimination requires development of novel strategies targeting the parasite sexual stages (gametocytes) to interfere with parasite transmission. The formation of Plasmodium falciparum gametocytes in the human host takes several days in which immature gametocyte-infected erythrocytes sequester in the bone marrow, and appear only as mature stages in the peripheral blood. The release and persistence in bloodstream are prerequisites for mature gametocytes to be taken up by mosquitoes and ensure parasite transmission. Our team has shown that release into the blood circulation is concomitant with an increase in infected erythrocyte deformability that allows mature gametocytes to circulate through the spleen (Tiburcio et al, Blood 2012). This process plays a key role in P. falciparum gametocyte development in the host and may represent novel and unconventional targets for interfering with parasite transmission: interventions targeting mechanisms that regulate gametocyte deformability would promote clearance of mature gametocytes by the spleen and reduce their ability to circulate in peripheral blood, thereby opening novel avenues in the present strategies to reduce parasite transmission.
Our goal is to decipher the cellular mechanisms underlying sequestration and circulation of P. falciparum gametocytes in the human host, and to establish that these mechanisms may be new targets to block malaria parasite transmission. Our work is oriented in 3 main axes:
1) Decipher the cellular mechanisms underlying sequestration and circulation of P. falciparum gametocytes.
We propose to use novel experimental approaches combining nanomechanics, cellular biology and in vivo imaging in humanized mice to unravel transmigration mechanisms through bone marrow endothelium and gametocytes interactions with erythroid progenitor cells in the bone marrow parenchyma. This work will allow to decipher the role of cellular deformability and adhesive properties in gametocyte sequestration and release into the bloodstream, and to identify new parasite proteins and signalling pathways involved in these process that could be targeted to block P. falciparum transmission.
2) Develop an in vivo model for Plasmodium falciparum transmission.
We have recently developed a humanized mouse model that allow the complete sexual development P. falciparum. These mice might be a convenient model to investigate P. falciparum gametocytes interactions with the bone marrow and the spleen, and they may facilitate the discovery of new transmission-blocking drugs.
3) Generate a novel multi-stage antimalarial drug with therapeutic and transmission-blocking activity.
We have shown that the phosphodiesterase (PDE) inhibitor sildenafil (Viagra) impairs the circulation of mature gametocytes in an in vitro model for splenic retention and thus may favor their elimination by the spleen in humans (Ramdani et al, Plos pathogens 2015). We propose to generate PDE inhibitors specific for P. falciparum and to evaluate their efficacy to impair P. falciparum asexual and sexual stages viability, circulation through the spleen in humanized mice, and transmission to mosquitoes. Combined with the wealth of data available about the FDA-approved drug sildenafil, expected results will pave the way for the set-up of a clinical trial in gametocyte carriers, that could allow to rapidly demonstrate the proof of concept of PDE inhibitors efficacy against P. falciparum transmission in humans.
The deformability of gametocyte-infected erythrocytes, facilitated when the cAMP pathway is inhibited, allows them to circulate freely through the spleen and remain accessible to mosquitoes in the blood circulation (top). The action of Viagra increases the stiffness of infected erythrocytes by activating the cAMP pathway, preventing their passage through the spleen endothelium and clearing the parasites from the blood circulation (bottom).
Since 2014, two post-doc scientists (Bernina Naissant and Giulia Manzoni), three engineers (Florian Dupuy, Audrey Lorthiois and Lina Gomez), one technician (Yoann Duffier), one PhD student (Gaëlle Neveu) and one Master student (Anthony Marteau) are involved in these programs.
- TV5 Monde, 64' Le Monde en Français (9/5/2015)
- France 5, Le magazine de la santé (11/05/2015),
- France Inter, La tête au Carré (8/5/2015),
- France Inter, le billet de Nicole Ferroni (12/5/2015),
- La Voix de l’Amérique (18/5/2015),
- Le Monde (8/5/2015), Du Viagra pour enrayer la transmission du paludisme (8/5/2015),
- Mediapart (8/5/2015), La piste du Viagra contre le paludisme
- The Sydney morning Herald (16/5/2015), Viagra slows the spread of malaria, study find
- O Globo (18/5/201), Viagra pode ajudar no combate da malaria
These programs are supported by the Fondation pour la Recherche Médicale, the Fondation de France, the Bill and Melinda Gates Foundation, the ATIP-Avenir program of CNRS and the labex GR-Ex.
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