title: Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factors that control it.
abstract: IFN-γ is a major cytokine that mediates resistance against the intracellular parasite Toxoplasma gondii. The p65 guanylate-binding proteins (GBPs) are strongly induced by IFN-γ. We studied the behavior of murine GBP1 (mGBP1) upon infection with T. gondii in vitro and confirmed that IFN-γ-dependent re-localization of mGBP1 to the parasitophorous vacuole (PV) correlates with the virulence type of the parasite. We identified three parasitic factors, ROP16, ROP18, and GRA15 that determine strain-specific accumulation of mGBP1 on the PV. These highly polymorphic proteins are held responsible for a large part of the strain-specific differences in virulence. Therefore, our data suggest that virulence of T. gondii in animals may rely in part on recognition by GBPs. However, phagosomes or vacuoles containing Trypanosoma cruzi did not recruit mGBP1. Co-immunoprecipitation revealed mGBP2, mGBP4, and mGBP5 as binding partners of mGBP1. Indeed, mGBP2 and mGBP5 co-localize with mGBP1 in T. gondii-infected cells. T. gondii thus elicits a cell-autonomous immune response in mice with GBPs involved. Three parasitic virulence factors and unknown IFN-γ-dependent host factors regulate this complex process. Depending on the virulence of the strains involved, numerous GBPs are brought to the PV as part of a large, multimeric structure to combat T. gondii.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Virreira Winter
authors.forename: Wendy
authors.initials: W
authors.lastname: Niedelman
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jensen
authors.forename: Emily E
authors.initials: EE
authors.lastname: Rosowski
authors.forename: Lindsay
authors.initials: L
authors.lastname: Julien
authors.forename: Eric
authors.initials: E
authors.lastname: Spooner
authors.forename: Kacey
authors.initials: K
authors.lastname: Caradonna
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Burleigh
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010588:Phagosomes / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism; D014122:Toxoplasma / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000469:parasitology*
chemical_list: D000953:Antigens, Protozoan; C490288:Gbp2b protein, mouse; D015800:Protozoan Proteins; D007371:Interferon-gamma; D006160:Guanosine Triphosphate; D011505:Protein-Tyrosine Kinases; C552524:Rop16 protein, Toxoplasma gondii; D017346:Protein Serine-Threonine Kinases; C556793:ROP18 protein, Toxoplasma gondii; D019204:GTP-Binding Proteins; C452200:Gbp2 protein, mouse; C472531:Gbp5 protein, mouse