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Infection des hépatocytes par Plasmodium : rôle des protéines de micronèmes des sporozoïtes

Abstract : Infection with the Plasmodium parasite begins with the injection of sporozoites by an Anopheles mosquito. The first target is the liver where the parasite replicates as a pre-requisite to the development of pathogenic blood stage infection. In the liver, sporozoites penetrate hepatocytes forming a parasitophorous vacuole in which the parasite multiplies. This step, the productive invasion, involves parasitic factors and host proteins, particularly CD81, but the underlying mechanisms remain largely unknown. To facilitate monitoring of sporozoite invasion, we generated novel transgenic fluorescent parasites, using a new selection strategy named GOMO (gene out marker out) in the rodent parasite P. yoelii. The use of this transgenic parasite and of host cell lines permissive or not to infection, has allowed us to better characterize the cellular and molecular mechanisms involved during invasion. We have confirmed that the productive invasion is preceded by a cell traversal phase. We discovered and characterized the formation of transient vacuoles during this step, before formation of the parasitophorous vacuole. Our results uncovered that the perforin-like protein (PLP1) mediates sporozoite egress from transient vacuoles and escape from degradation by the cell lysosomes. Once activated, the sporozoites switch from the mode of cell traversal to productive invasion. We show that CD81 plays a role in the productive invasion. CD81 is necessary to induce the secretion of rhoptries proteins, involved in the formation of the moving junction, a structure through which the parasite glides to enter the cell. We could also show that another hepatocyte protein, SR-B1 (scavenger receptor B1), defines a CD81-independent pathway for P. berghei and P. vivax infection. Using an original genetic approach, we have shown that two sporozoite micronemal proteins, P52 and P36, play a role in the entry via CD81 and SR-B1, and highlighted a functional link between P36 and entry via SR-B1. Finally, we have developed several genetic approaches to target ama1 gene in P. yoelii, which encodes a protein involved in the formation of the moving junction. Altogether, our results contribute to improve our understanding of the mechanisms of sporozoite invasion, and open interesting perspectives for the development of novel vaccine strategies.
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  • HAL Id : tel-01728727, version 1

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Selma Topçu. Infection des hépatocytes par Plasmodium : rôle des protéines de micronèmes des sporozoïtes. Parasitologie. Université Pierre et Marie Curie - Paris VI, 2016. Français. ⟨NNT : 2016PA066080⟩. ⟨tel-01728727⟩

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