title: Migratory activation of parasitized dendritic cells by the protozoan Toxoplasma gondii 14-3-3 protein.
abstract: The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon infection, parasitized dendritic cells (DCs) and microglia exhibit a hypermigratory phenotype in vitro that has been associated with enhancing parasite dissemination in vivo in mice. One unresolved question is how parasites commandeer parasitized cells to achieve systemic dissemination by a 'Trojan-horse' mechanism. By chromatography and mass spectrometry analyses, we identified an orthologue of the 14-3-3 protein family, T. gondii 14-3-3 (Tg14-3-3), as mediator of DC hypermotility. We demonstrate that parasite-derived polypeptide fractions enriched for Tg14-3-3 or recombinant Tg14-3-3 are sufficient to induce the hypermotile phenotype when introduced by protein transfection into murine DCs, human DCs or microglia. Further, gene transfer of Tg14-3-3 by lentiviral transduction induced hypermotility in primary human DCs. In parasites expressing Tg14-3-3 in a ligand-regulatable fashion, overexpression of Tg14-3-3 was correlated with induction of hypermotility in parasitized DCs. Localization studies in infected DCs identified Tg14-3-3 within the parasitophorous vacuolar space and a rapid recruitment of host cell 14-3-3 to the parasitophorous vacuole membrane. The present work identifies a determinant role for Tg14-3-3 in the induction of the migratory activation of immune cells by T. gondii. Collectively, the findings reveal Tg14-3-3 as a novel target for an intracellular pathogen that acts by hijacking the host cell's migratory properties to disseminate.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 09, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Weidner
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 09, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden.
authors.forename: Sachie
authors.initials: S
authors.lastname: Kanatani
authors.affiliation: Science for Life Laboratories, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Uchtenhagen
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.|Centro de Investigacion Biomedica, Faculty of Medicine, Universidad de los Andes, ​755000, Santiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Varas-Godoy
authors.affiliation: Science for Life Laboratories, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Sweden.
authors.forename: Tim
authors.initials: T
authors.lastname: Schulte
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, 02467, USA.
authors.forename: Klemens
authors.initials: K
authors.lastname: Engelberg
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, 02467, USA.
authors.forename: Marc-Jan
authors.initials: MJ
authors.lastname: Gubbels
authors.affiliation: Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, M1C 1A4, Canada.
authors.forename: He Song
authors.initials: HS
authors.lastname: Sun
authors.affiliation: Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, M1C 1A4, Canada.
authors.forename: Rene E
authors.initials: RE
authors.lastname: Harrison
authors.affiliation: Science for Life Laboratories, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Sweden.
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 09, Stockholm, Sweden. antonio.barragan@su.se.|Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden. antonio.barragan@su.se.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barragan
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000469:parasitology / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D008810:Mice, Inbred C57BL; D015800:Protozoan Proteins / Q000502:physiology*; D014122:Toxoplasma / Q000502:physiology*; D014617:Vacuoles / Q000378:metabolism / Q000469:parasitology
chemical_list: D048948:14-3-3 Proteins; D015800:Protozoan Proteins