Format

Send to

Choose Destination
Cell Microbiol. 2016 Nov;18(11):1537-1550. doi: 10.1111/cmi.12595. Epub 2016 May 6.

Migratory activation of parasitized dendritic cells by the protozoan Toxoplasma gondii 14-3-3 protein.

Author information

1
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 09, Stockholm, Sweden.
2
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden.
3
Science for Life Laboratories, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Sweden.
4
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
5
Centro de Investigacion Biomedica, Faculty of Medicine, Universidad de los Andes, ​755000, Santiago, Chile.
6
Department of Biology, Boston College, Chestnut Hill, MA, 02467, USA.
7
Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, M1C 1A4, Canada.
8
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 09, Stockholm, Sweden. antonio.barragan@su.se.
9
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 86, Stockholm, Sweden. antonio.barragan@su.se.

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.

PMID:
27018989
PMCID:
PMC5040621
DOI:
10.1111/cmi.12595
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center