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Study of factors governing the invasive and replicative modes in Apicomplexa

English title Study of factors governing the invasive and replicative modes in Apicomplexa
Applicant Soldati-Favre Dominique
Number 131073
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 Medical Microbiology
Start/End 01.04.2010 - 31.03.2013
Approved amount 675'000.00
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All Disciplines (5)

Discipline
Medical Microbiology
Biochemistry
Cellular Biology, Cytology
Molecular Biology
Experimental Microbiology

Keywords (14)

apicomplexa; parasite; toxoplasma gondii; plasmodium falciparum; plasmodium berghei; motility; Plasmodium; Toxoplasma; invasion; division; motor; adhesin; actin; protease

Lay Summary (English)

Lead
Lay summary
Lead: The Apicomplexa groups obligate intracellular pathogens responsible for severe diseases such as malaria and toxoplasmosis. This project aims at studying the molecular mechanisms underlining parasite lytic cycle, which involves active host cell entry, intracellular replication and egress from host cells.Résumé:Gliding motility is a unique attribute of the phylum Apicomplexa, which is crucial for parasite migration across biological barriers, host cell invasion and egress from infected cells. Timing, duration and orientation of gliding motility are tightly regulated by i) two formins that spatially control actin filaments polymerization ii) assembly and disassembly of myosin motor complexes, which is governed by posttranslational modifications resulting from a calcium-dependent signaling cascade, Host cell invasion involves the recognition host cell receptors by specialized parasite adhesins, followed by disengagement of these adhesins through the action of parasite rhomboid proteases. The process culminates with a switching mechanism from the invasive- to the replicative-mode. There a complex spatial and temporal interplay between the components of host cell recognition, gliding machinery, and parasite replication.But: Our studies focus on the regulators of actin dynamics, the myosin motors, the transmembrane micronemal proteins complexes and the proteases involved in their processing. The aim is to elucidate how these classes of proteins are connected together and act in concert to control invasion, replication and egress in apicomplexans. Ultimately, the outcome of those investigations should lead to the identification of novel targets for intervention against these lethal or debilitating pathogens.Signification: Apicomplexa are eukaryotic organisms posing serious public health concerns and veterinary problems. They have evolved a broad variety of highly sophisticated strategies evolved to subvert host processes in order to maximize access to nutrients, assure dissemination and transmission, neutralize host defenses, and avoid destruction. A fundamental understanding of the basic molecular mechanisms of parasitism is a prerequisite to defeat them.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The Toxoplasma Protein ARO Mediates the Apical Positioning of Rhoptry Organelles, a Prerequisite for Host Cell Invasion
Mueller Christina, Klages Natacha, Jacot Damien, Santos M Joana, Cabrera Ana, Gilberger W. Tim, Dubremetz Jean Fracois, Soldati-Favre Dominique (2013), The Toxoplasma Protein ARO Mediates the Apical Positioning of Rhoptry Organelles, a Prerequisite for Host Cell Invasion, in Cell Host & Microbe, 13, 289-301.
Toxoplasma gondii myosin F, an essential motor for centrosomes positioning and apicoplast inheritance
Jacot Damien, Daher Wassim, Soldati-Favre Dominique (2013), Toxoplasma gondii myosin F, an essential motor for centrosomes positioning and apicoplast inheritance, in EMBO Journal , 32, 1702-1716.
Galactose recognition by the apicomplexan parasite Toxoplasma gondii.
Marchant Jan, Cowper Ben, Liu Yan, Lai Livia, Pinzan Camila, Marq Jean Baptiste, Friedrich Nikolas, Sawmynaden Kovilen, Liew Lloyd, Chai Wengang, Childs Robert A, Saouros Savvas, Simpson Peter, Roque Barreira Maria Cristina, Feizi Ten, Soldati-Favre Dominique, Matthews Stephen (2012), Galactose recognition by the apicomplexan parasite Toxoplasma gondii., in The Journal of biological chemistry, 287(20), 16720-16733.
Molecular Characterization of Toxoplasma gondii Formin 3, an Actin Nucleator Dispensable for Tachyzoite Growth and Motility
Daher W, Klages N, Carlier MF, Soldati-Favre D (2012), Molecular Characterization of Toxoplasma gondii Formin 3, an Actin Nucleator Dispensable for Tachyzoite Growth and Motility, in EUKARYOTIC CELL, 11(3), 343-352.
Toxoplasma gondii Profilin Acts Primarily To Sequester G-Actin While Formins Efficiently Nucleate Actin Filament Formation in Vitro
Skillman KM, Daher W, Ma CI, Soldati-Favre D, Sibley LD (2012), Toxoplasma gondii Profilin Acts Primarily To Sequester G-Actin While Formins Efficiently Nucleate Actin Filament Formation in Vitro, in BIOCHEMISTRY, 51(12), 2486-2495.
Intramembrane Cleavage of AMA1 Triggers Toxoplasma to Switch from an Invasive to a Replicative Mode
Santos JM, Ferguson DJP, Blackman MJ, Soldati-Favre D (2011), Intramembrane Cleavage of AMA1 Triggers Toxoplasma to Switch from an Invasive to a Replicative Mode, in SCIENCE, 331(6016), 473-477.
Unusual Anchor of a Motor Complex (MyoD-MLC2) to the Plasma Membrane of Toxoplasma gondii
Polonais V, Foth BJ, Chinthalapudi K, Marq JB, Manstein DJ, Soldati-Favre D, Frenal K (2011), Unusual Anchor of a Motor Complex (MyoD-MLC2) to the Plasma Membrane of Toxoplasma gondii, in TRAFFIC, 12(3), 287-300.
Concerted Action of Two Formins in Gliding Motility and Host Cell Invasion by Toxoplasma gondii
Daher Wassim, Plattner Fabienne, Carlier Marie France, Soldati-Favre Dominique (2010), Concerted Action of Two Formins in Gliding Motility and Host Cell Invasion by Toxoplasma gondii, in PloS Pathogens, 6, e1001132-e1001146.
Functional Dissection of the Apicomplexan Glideosome Molecular Architecture
Frenal K, Polonais V, Marq JB, Stratmann R, Limenitakis J, Soldati-Favre D (2010), Functional Dissection of the Apicomplexan Glideosome Molecular Architecture, in CELL HOST & MICROBE, 8(4), 343-357.
Toxoplasma gondii transmembrane microneme proteins and their modular design
Sheiner L, Santos JM, Klages N, Parussini F, Jemmely N, Friedrich N, Ward GE, Soldati-Favre D (2010), Toxoplasma gondii transmembrane microneme proteins and their modular design, in MOLECULAR MICROBIOLOGY, 77(4), 912-929.

Collaboration

Group / person Country
Types of collaboration
Stephen Matthews Imperial College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Julian Rayner Sanger Institute Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Marie France Carlier, CNRS France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Joint Conference of HGM 2013 & 21st ICG Talk given at a conference Access and adaptation to an intracellular niche the Apicomplexa way 13.04.2013 Singapore, Singapore Soldati-Favre Dominique;
The 11th Awaji International Forum on Infection and Immunity Talk given at a conference Adaptation to an obligate intracellular life style: the Apicomplexa way 11.09.2012 Japan, Japan Jacot Damien; Soldati-Favre Dominique;
Molecular Approaches to Malaria 2012 Talk given at a conference Actinomyosin-based motility and organellar positioning in Toxoplasma 19.02.2012 Lorne, Australia, Australia Jacot Damien; Soldati-Favre Dominique;
Organized Indo-Swiss Joint symposium Talk given at a conference Mechanisms controlling motility and host cell invasion by the Apicomplexa 03.11.2011 Jawaharlal Nehru University, New Delhi, India, India Soldati-Favre Dominique;
Meeting of the Spanish Society of Biochemistry and Molecular Biology (XXXIV SEBBM) Talk given at a conference Life inside a vacuole 05.09.2011 Barcelona Spain, Spain Soldati-Favre Dominique;
International Meeting On Cell Biology Of Pathogens Talk given at a conference Mitochondrial translation in absence of local tRNA aminoacylation in Apicomplexa 07.08.2011 Guaruja, São Paulo, Brazil, Brazil Oppenheim Rebecca Diane; Limenitakis Julien;
FEBS 2011. 36th Congress "Biochemistry for Tomorrow's Medicine" Talk given at a conference Molecular events governing the lytic cycle in Apicomplexa 25.06.2011 Torino Italy, Italy Soldati-Favre Dominique;
Indo-Swiss Symposium on Infectious Diseases Talk given at a conference Mechanisms controlling motility and host cell invasion by the Apicomplexans 02.05.2011 EPFL Lausanne Switzerland, Switzerland Soldati-Favre Dominique;
10th International Coccidiosis Conference Talk given at a conference Biology of Toxoplasma 08.10.2010 Guangzhou, China , China Soldati-Favre Dominique;
International Congress of Parasitology ICOPA XII Talk given at a conference Apicomplexan host cell invasion 15.08.2010 Melbourne Australia, Australia Soldati-Favre Dominique;
Gordon Research Conference on the Biology of Host-Parasite Interactions Talk given at a conference Motility and Invasion in Apicomplexa 27.06.2010 Salve Regina College in Newport, USA , United States of America Soldati-Favre Dominique;
COST Action meeting -CM0801 Talk given at a conference Protein Palmitoylation in Apicomplexa 28.05.2010 Siena,Italy, Italy Kemp Louise; Soldati-Favre Dominique;


Awards

Title Year
HHMI Senior International Research Scholar 2012
Pfizer Prize 2012 2012
EMBO member 2011

Associated projects

Number Title Start Funding scheme
116722 Molecular dissection of gliding motility and host cell invasion by the apicomplexa 01.04.2007 Project funding (Div. I-III)

Abstract

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. Members of Apicomplexa are obligate intracellular parasites that have elaborated a unique and powerful mode of host cell entry. In the absence of locomotive organelles such as cilia or flagella, the invasive forms of these parasites exhibit an unusual form of substrate-dependent motility that is essential for host cell invasion and establishment of infection. Genetics studies have established that gliding motility and cell penetration by T. gondii needs intact parasite actin filaments (Dobrowolski and Sibley, 1996) and is powered by the action an essential class XIV myosin motor, which propels the parasite into host cells (Meissner et al., 2002b). Drugs that interfere with actin polymerization or stabilize actin filaments have profound effects on motility (Wetzel et al., 2003), yet the mechanism by which Apicomplexa control actin polymerization is unknown. Gliding is also associated with the discharge of several complexes of proteins (MICs) that are stored in the secretory organelles called micronemes. The MICs complexes are released on parasite surface upon a raise in parasite intracellular calcium level, they bind to host cell receptors and contribute critically to attachment, motility and invasion. Remarkably, most MICs are proteolytically cleaved during their biogenesis and/or post-exocytosis. Microneme protein protease 1 (MPP1) a rhomboid protease, is responsible for the intramembrane proteolytic cleavage leading to the release of the MICs from the parasite surface and indirect evidence suggest that this activity is essential for invasion in T. gondii (Brossier et al., 2003) and in P. falciparum (O'Donnell R et al., 2006). Despite some major progress a number of unresolved issues still persist: how is F-actin dynamics regulated? How many myosin motors contribute to the three forms of Toxoplasma motility during invasion? What is the molecular basis of T. gondii broad host range specificity? What is the mechanistic significance of microneme proteins shedding during invasion?Toxoplasma is an attractive model system due to its ease of experimental use, excellent tools for cellular and even biochemical studies, and well-developed genetic systems (Roos et al., 1994) and because the gliding mechanism is very conserved, the major findings hold true for other members of the Phylum including Plasmodium species responsible for malaria.
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