Host Institution : CNRS
Laboratoire : Institut Jean Roget
Appel à projet : Consolidator (LS6)
Nom du Projet : HOSTINGTOXO – Toxoplasma gondii secretes an armada of effector proteins to co-opt its host cell transcriptome and microRNome to promote sustained parasitism
Montant : 1,97 M€
Toxoplasma gondii is a widespread obligate intracellular protozoan parasite causing toxoplasmosis, a severe disease in immunocompromised or congenitally infected humans. It can infect any type of nucleated cells and grow inside a parasitophorous vacuole (PV) from where it directs profound changes in their transcriptome, proteome and microRNome. During invasion and creation of the PV membrane, apically oriented organelles called micronemes and rhoptries are discharged, followed later by release of dense granules content (DG). Recent advances have highlighted few strain-specific parasite effectors released from the rhoptry into the host cells where they neutralize cell autonomous immunity defences or subvert the host cell transcriptome thereby governing the fate of immune response and disease outcomes. Considering the magnitude of the repertoire of mRNA- and microRNA-encoding genes that is differentially regulated in host cells, it seems certain that other critical rhoptry- and DG-resident proteins that interact with host signaling pathways await discovery. By integrating diverse genomic-scale analyses and using reverse genetic, we identify novel DG proteins that are singularly exported beyond the tachyzoites-hosting PV to the host cell nucleus, thus extending the scope of the function of DG proteins beyond their dedicated role in vacuole formation. This collection of novel parasite effectors will be invaluable towards our goal of understanding how T. gondii actively remodels the genome expression of its hosting cell with profound and coupled impact on both parasite developmental process and the host immune response. We propose i) to characterize thoroughly the function of novel effector proteins secreted by T. gondii and ii) to explore how their synergistic or antagonist effects on host gene regulation contribute to promote sustained parasitism. An original line of research will be dedicated to determine by which means T. gondii re-programs the host microRNome.