Toxoplasma gondii Parasitophorous Vacuole Membrane-Associated Dense Granule Proteins Orchestrate Chronic Infection and GRA12 Underpins Resistance to Host Gamma Interferon

Autor: Marie-France Cesbron-Delauw, Valeria Bellini, Camille Rak, Barbara A. Fox, Graciane Petre, Leah M. Rommereim, David J. Bzik, Gregory A. Taylor, Alejandra Falla, Corinne Mercier, Rebekah B. Guevara, Jean-François Dubremetz, Viviana Cantillana
Přispěvatelé: Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology and Immunology, Dartmouth Medical School, Department of Molecular Medicine, Mayo Clinic College of Medicine, Barrière Naturelle et Infectiosité (TIMC-BNI ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-IMAG-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-IMAG-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Duke University [Durham], Université Montpellier 2 - Sciences et Techniques (UM2), Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Génomique et Évolution des Microorganismes (TIMC-IMAG-GEM)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
[SDV]Life Sciences [q-bio]
Protozoan Proteins
membrane proteins
Virulence factor
innate immunity
ComputingMilieux_MISCELLANEOUS
Cells
Cultured
Mice
Knockout
0303 health sciences
biology
Virulence
QR1-502
3. Good health
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
Host-Pathogen Interactions
Female
Toxoplasma
Toxoplasmosis
Research Article
Cell Survival
Virulence Factors
Toxoplasma gondii
dense granule
Microbiology
Host-Microbe Biology
03 medical and health sciences
Interferon-gamma
Immune system
Virology
parasitic diseases
Animals
030304 developmental biology
Immune Evasion
Innate immune system
030306 microbiology
Intracellular Membranes
Models
Theoretical
biology.organism_classification
chronic infection
Survival Analysis
Mice
Inbred C57BL
Chronic infection
Disease Models
Animal
Membrane protein
Vacuoles
Dense granule
Gene Deletion
Zdroj: mBio
mBio, 2019, 10 (4), ⟨10.1128/mBio.00589-19⟩
mBio, American Society for Microbiology, 2019, 10 (4), ⟨10.1128/mBio.00589-19⟩
mBio, Vol 10, Iss 4 (2019)
mBio, Vol 10, Iss 4, p e00589-19 (2019)
ISSN: 2150-7511
2161-2129
DOI: 10.1128/mBio.00589-19⟩
Popis: Toxoplasma gondii cysts reactivate during immune deficiency and cause fatal encephalitis. Parasite molecules that coordinate the development of acute and chronic infection are poorly characterized. Here, we show that many intravacuolar network membrane and parasitophorous vacuole membrane-associated dense granule (GRA) proteins orchestrate the development of chronic cysts in vivo. A subset of these GRA proteins also modulate acute virulence, and one protein that associates with the intravacuolar network membranes, namely GRA12, was identified as a major virulence factor required for parasite resistance to host gamma interferon (IFN-γ). Our results revealed that many parasitophorous vacuole membrane and intravacuolar network membrane-associated GRA proteins are essential for successful chronic infection.
Toxoplasma gondii evades host immunity to establish a chronic infection. Here, we assessed the role of parasitophorous vacuole (PV) membrane (PVM)- and intravacuolar network (IVN) membrane-localized dense granule (GRA) proteins in the development of acute and chronic Toxoplasma infection. Deletion of PVM-associated GRA3, GRA7, GRA8, and GRA14 or IVN membrane-associated GRA2, GRA9, and GRA12 in the low-virulence type II Prugniaud (Pru) strain induced severe defects in the development of chronic-stage cysts in vivo without affecting the parasite growth rate or the ability to differentiate into cysts in vitro. Acute virulence of the PruΔgra2, PruΔgra3, and PruΔgra4 mutants was reduced but not abolished. In contrast, the PruΔgra12 mutant was avirulent in mice and PruΔgra12 parasites failed to establish a chronic infection. High-virulence type I strain RHΔgra12 parasites also exhibited a major defect in acute virulence. In gamma interferon (IFN-γ)-activated macrophages, type I RHΔgra12 and type II PruΔgra12 parasites resisted the coating of the PVM with host immunity-related GTPases as effectively as the parental type I RHΔku80 and type II PruΔku80 strains, respectively. Despite this resistance, Δgra12 PVs ultimately succumbed to IFN-γ-activated host cell innate immunity. Our findings uncover a key role for GRA12 in mediating resistance to host IFN-γ and reveal that many other IVN membrane-associated GRA proteins, as well as PVM-localized GRA proteins, play important roles in establishing chronic infection.
Databáze: OpenAIRE
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