title: Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development.
abstract: The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome- and autophagy-derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella-containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations.
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Martinez
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Allombert
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Franck
authors.initials: F
authors.lastname: Cantet
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Anissa
authors.initials: A
authors.lastname: Lakhani
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Naresh
authors.initials: N
authors.lastname: Yandrapalli
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Aymeric
authors.initials: A
authors.lastname: Neyret
authors.affiliation: Defence Science and Technology Laboratory, Porton Down SP4 0JQ, United Kingdom.
authors.forename: Isobel H
authors.initials: IH
authors.lastname: Norville
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Cyril
authors.initials: C
authors.lastname: Favard
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France;
authors.forename: Delphine
authors.initials: D
authors.lastname: Muriaux
authors.affiliation: CNRS, Formation de Recherche en Évolution 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université Montpellier, 34090 Montpellier, France; matteo.bonazzi@cpbs.cnrs.fr.
authors.forename: Matteo
authors.identifier: 0000-0001-5499-8759
authors.initials: M
authors.lastname: Bonazzi
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D016997:Coxiella burnetii / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D007915:Lepidoptera / Q000382:microbiology; D009154:Mutation; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D018129:Phosphatidylinositol Phosphates; D010718:Phosphatidylserines; C055525:phosphatidylinositol 3-phosphate
keywords: Coxiella burnetii; host–pathogen interactions; phosphoinositides