Project

Back to overview

An integrated approach to elucidate the molecular mechanisms governing host cell invasion by the Apicomplexa

English title An integrated approach to elucidate the molecular mechanisms governing host cell invasion by the Apicomplexa
Applicant Soldati-Favre Dominique
Number 166678
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.04.2016 - 31.03.2019
Approved amount 834'000.00
Show all

Keywords (9)

Myosins; proteolytic processing ; Invasion; F-actin; Attachment ; signalling; Apicomplexa; proteases; Motility

Lay Summary (French)

Lead
Une approche intégrée visant à élucider les mécanismes moléculaires régissant la migration à travers les barrières biologiques et l'invasion des cellules hôtes chez les Apicomplexes
Lay summary

Le mouvement est une propriété intrinsèque à tous les organismes vivants. Au cours de l’évolution, ils ont élaboré des mécanismes sophistiqués autour de protéines du cytosquelette et de moteurs moléculaires pour générer diverses formes de motilité cellulaire.  Les Apicomplexes sont d'une considérable importance médicale et vétérinaire, étant responsable de maladies chez les humains et les animaux. Ces parasites intracellulaires obligatoires partagent une forme unique de motilité glissante essentielle à leur survie et dissémination. Ce mode de locomotion propulse le parasite à l’intérieur des cellules hôtes et conduit à la formation d’une vacuole parasitophore non-fusiogénique. Ce processus implique la libération de matériel membranaire et protéinique incluant des adhésines par les organelles de sécrétion appelées micronèmes  et rhoptries. Les adhésines permettent d’établir une interaction forte avec les récepteurs de la cellule hôte et la formation d’une jonction circulaire, mobile. La motilité est  engendrée par la translocation de ces adhésines transmembranaires vers le pôle postérieur du parasite sous l’action  concertée de moteurs de type myosine. La présence d'un connecteur capable d’établir un pont entre le cytosquelette d’actine et les adhésines est impérative.  Au cours de l’invasion le conoïde, une organelle motile, composée d’anneaux de tubulines extrude à l’extrémité apicale du parasite mais son rôle est incompris.

Ce projet vise à élucider la contribution du conoïde, les mécanismes de signalisation conduisant à la libération des adhésines, le processus de contrôle de la polymérisation de l’actine et de  l’activation des moteurs afin de percer comment ces phénomènes complexes sont orchestrés de façon concertée pour culminer à l’invasion active de la cellule hôte.  Une compréhension plus approfondie du mécanisme d'invasion devrait permettre d’identifier le talon d’Achille de ces parasites, susceptible de servir de cible thérapeutique.

Direct link to Lay Summary Last update: 23.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Three F-actin assembly centers regulate organelle inheritance, cell-cell communication and motility in Toxoplasma gondii
Tosetti Nicolò, Dos Santos Pacheco Nicolas, Soldati-Favre Dominique, Jacot Damien (2019), Three F-actin assembly centers regulate organelle inheritance, cell-cell communication and motility in Toxoplasma gondii, in eLife, 8, e42669.
Phosphatidic acid governs natural egress in Toxoplasma gondii via a guanylate cyclase receptor platform
Bisio Hugo, Lunghi Matteo, Brochet Mathieu, Soldati-Favre Dominique (2019), Phosphatidic acid governs natural egress in Toxoplasma gondii via a guanylate cyclase receptor platform, in Nature Micro, 420.
Structural Basis of Phosphatidic Acid Sensing by APH in Apicomplexan Parasites
Darvill Nick, Dubois David J., Rouse Sarah L., Hammoudi Pierre-Mehdi, Blake Tom, Benjamin Stefi, Liu Bing, Soldati-Favre Dominique, Matthews Steve (2018), Structural Basis of Phosphatidic Acid Sensing by APH in Apicomplexan Parasites, in Structure, 26(8), 1059-1071.e6.
Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases
Mukherjee Budhaditya, Tessaro Francesca, Vahokoski Juha, Kursula Inari, Marq Jean-Baptiste, Scapozza Leonardo, Soldati-Favre Dominique (2018), Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases, in The {EMBO} Journal, 98047-98047.
Structural Basis of Phosphatidic Acid Sensing by APH in Apicomplexan Parasites
(2018), Structural Basis of Phosphatidic Acid Sensing by APH in Apicomplexan Parasites, in Structure, 1059.
Toxoplasma gondii TFP1 is an essential transporter family protein critical for microneme maturation and exocytosis
Hammoudi Pierre-Mehdi, Maco Bohumil, Dogga Sunil Kumar, Frénal Karine, Soldati-Favre Dominique (2018), Toxoplasma gondii TFP1 is an essential transporter family protein critical for microneme maturation and exocytosis, in Molecular Microbiology, 225-244.
Functions of myosin motors tailored for parasitism
Mueller Christina, Graindorge Arnault, Soldati-Favre Dominique (2017), Functions of myosin motors tailored for parasitism, in Current Opinion in Microbiology, 40, 113-122.
Gliding motility powers invasion and egress in Apicomplexa
Frénal Karine, Dubremetz Jean-François, Lebrun Maryse, Soldati-Favre Dominique (2017), Gliding motility powers invasion and egress in Apicomplexa, in Nature Reviews Microbiology, 15(11), 645-660.
A druggable secretory protein maturase of Toxoplasma essential for invasion and egress
Dogga Sunil Kumar, Mukherjee Budhaditya, Jacot Damien, Kockmann Tobias, Molino Luca, Hammoudi Pierre-Mehdi, Hartkoorn Ruben C, Hehl Adrian B, Soldati-Favre Dominique (2017), A druggable secretory protein maturase of Toxoplasma essential for invasion and egress, in eLife, 6, 27480.
Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
Jia Yonggen, Marq Jean-Baptiste, Bisio Hugo, Jacot Damien, Mueller Christina, Yu Lu, Choudhary Jyoti, Brochet Mathieu, Soldati-Favre Dominique (2017), Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii, in The {EMBO} Journal, 36(21), 3250-3267.
Myosin-dependent cell-cell communication controls synchronicity of division in acute and chronic stages of Toxoplasma gondii
Frénal Karine, Jacot Damien, Hammoudi Pierre-Mehdi, Graindorge Arnault, Maco Bohumil, Soldati-Favre Dominique (2017), Myosin-dependent cell-cell communication controls synchronicity of division in acute and chronic stages of Toxoplasma gondii, in Nature Comm., 15710.
An Apicomplexan Actin-Binding Protein Serves as a Connector and Lipid Sensor to Coordinate Motility and Invasion
Jacot Damien, Tosetti Nicolò, Pires Isa, Stock Jessica, Graindorge Arnault, Hung Yu-Fu, Han Huijong, Tewari Rita, Kursula Inari, Soldati-Favre Dominique (2016), An Apicomplexan Actin-Binding Protein Serves as a Connector and Lipid Sensor to Coordinate Motility and Invasion, in Cell Host & Microbe, 20(6), 731-743.
A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa
Bullen Hayley E., Soldati-Favre Dominique (2016), A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa, in {FEBS} Letters, 590(15), 2469-2481.
Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma
Bullen Hayley~E., Jia Yonggen, Yamaryo-Botté Yoshiki, Bisio Hugo, Zhang Ou, Jemelin Natacha~Klages, Marq Jean-Baptiste, Carruthers Vern, Botté Cyrille~Y., Soldati-Favre Dominique (2016), Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma, in Cell Host {&} Microbe, 19(3), 349-360.
Structural and functional dissection ofToxoplasma gondiiarmadillo repeats only protein
Mueller Christina, Samoo Atta, Hammoudi Pierre-Mehdi, Klages Natacha, Kallio Juha Pekka, Kursula Inari, Soldati-Favre Dominique (2016), Structural and functional dissection ofToxoplasma gondiiarmadillo repeats only protein, in Journal of Cell Science, 129(5), 1031-1045.
The Conoid Associated Motor MyoH Is Indispensable for Toxoplasma gondii Entry and Exit from Host Cells
Graindorge Arnault, Frénal Karine, Jacot Damien, Salamun Julien, Marq Jean Baptiste, Soldati-Favre Dominique (2016), The Conoid Associated Motor MyoH Is Indispensable for Toxoplasma gondii Entry and Exit from Host Cells, in {PLoS} Pathog, 12(1), 1005388-1005388.
Toxoplasma gondii immune mapped protein 1 is anchored to the inner leaflet of the plasma membrane and adopts a novel protein fold
Jia Yonggen, Benjamin Stefi, Liu Qun, Xu Yingqi, Dogga Sunil Kumar, Liu Jing, Matthews Stephen, Soldati-Favre Dominique (2016), Toxoplasma gondii immune mapped protein 1 is anchored to the inner leaflet of the plasma membrane and adopts a novel protein fold, in Biochimica et Biophysica Acta ({BBA}) - Proteins and Proteomics, 208.

Collaboration

Group / person Country
Types of collaboration
Mathieu Borchet Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Inari KURSULA/ Department of Biomedicine, University of Bergen, Norway Norway (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Stephen Matthews/Imperial College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
ASBMB Alice and CC Wand Award in Parasitology 2019

Associated projects

Number Title Start Funding scheme
147118 Actomyosin-based motility and organelles biogenesis in Apicomplexans 01.04.2013 Project funding (Div. I-III)
170794 3D cryo-electron microscopy for analysis of macromolecular assemblies at atomic resolution 01.09.2017 R'EQUIP
177086 3D g(ated)STED super-resolution microscope 01.07.2018 R'EQUIP
147118 Actomyosin-based motility and organelles biogenesis in Apicomplexans 01.04.2013 Project funding (Div. I-III)
185325 An integrated approach to elucidate the molecular mechanisms governing host cell invasion and egress by the Apicomplexa 01.04.2019 Project funding (Div. I-III)
160702 Cyst wall formation: a persistent challenge in Toxoplasmosis 01.10.2015 Sinergia

Abstract

Motion is an intrinsic property of all living organisms and they have evolved diverse strategies to harness cytoskeletal structural and motor proteins to support and organise cellular movement. The protozoan parasites belonging to the phylum of Apicomplexa are of enormous medical and veterinary significance, being responsible for a wide variety of diseases in human and animals, including malaria, toxoplasmosis, coccidiosis and cryptosporidiosis. Host cell entry and egress are key events in the lytic cycle and dissemination of the Apicomplexa. These obligate intracellular parasites share a unique form of gliding motility, which is essential for their survival and infectivity. The substrate-dependent motion propels the parasite into host cell and across biological barriers hence contributing critically to spreading throughout the host. The basic mechanisms involved in parasite locomotion, host cell recognition, attachment and invasion are, to a large extent, conserved across the members of the phylum.The parasites release adhesins from apical regulated secretory organelles called micronemes and establish a tight interaction with host cell receptors forming a circular junction. Gliding motility is driven by the translocation of the membrane spanning microneme proteins (AMAs and MICs) toward the posterior pole of the parasite that is powered by a myosin motor complexe termed MyoA-glideosome which is anchored in the inner membrane complex (IMC). The model of gliding and invasion depends on the existence of a connector capable of binding to F-actin and linking it to the cytoplasmic tails of the MICs/AMAs while associated with their respective receptors. The rearward translocation of apically secreted adhesins also propels the parasite inside the host cell during invasion.This project aims at elucidating the mechanism of action of the glideosome and dissecting conoid protrusion, microneme exocytosis and secretory proteins maturation. The unchanged long-term objective is to provide a better understanding of how these complex events are orchestrated into a concerted action that culminates with the establishment of infection. The specific research plan is to embark on five specific objectives: I) Dissection of the mechanism triggering conoid protrusion II) Structure-function relationships analysis of the connector to determine how it interacts with its partners during motility and invasion III) Elucidation of the architecture of the glideosome IV) Mechanistic and structural dissection of phosphatidic acid as lipid mediator that trigger of microneme exocytosis V) investigation of the impact of rhoptry and microneme proteins proteolytic maturation upon their trafficking and function.Our overarching and long-term goal is to dissect the structure-function relationships of key invasion factors that ultimately could be targeted by new therapies. We will combine advance technologies for generation and molecular phenotyping of Toxoplasma mutants with state-of-the-art proteomics methods and crystallization efforts to identify the relevant interactomes and generate an in-depth understanding of the functional interactions and ultimately screen for small-molecule inhibitors that will block parasite dissemination.
-