title: Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii.
abstract: IFN-γ activates cells to restrict intracellular pathogens by upregulating cellular effectors including the p65 family of guanylate-binding proteins (GBPs). Here we test the role of Gbp1 in the IFN-γ-dependent control of T. gondii in the mouse model. Virulent strains of T. gondii avoided recruitment of Gbp1 to the parasitophorous vacuole in a strain-dependent manner that was mediated by the parasite virulence factors ROP18, an active serine/threonine kinase, and the pseudokinase ROP5. Increased recruitment of Gbp1 to Δrop18 or Δrop5 parasites was associated with clearance in IFN-γ-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Δrop18 mutants in IFN-γ-activated macrophages was reverted in Gbp1(-/-) cells, and decreased virulence of this mutant was compensated in Gbp1(-/-) mice, which were also more susceptible to challenge with type II strain parasites of intermediate virulence. These findings demonstrate that Gbp1 plays an important role in the IFN-γ-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense.
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Elizabeth M
authors: EM
authors: Selleck
authors: Sarah J
authors: SJ
authors: Fentress
authors: Wandy L
authors: WL
authors: Beatty
authors: Daniel
authors: D
authors: Degrandi
authors: Klaus
authors: K
authors: Pfeffer
authors: Herbert W
authors: HW
authors: Virgin
authors: John D
authors: JD
authors: Macmicking
authors: L David
authors: LD
authors: Sibley
mesh_terms: D000818:Animals; D000071187:Autophagy-Related Protein 5; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins; D014122:Toxoplasma / Q000276:immunology* / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000276:immunology* / Q000469:parasitology
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C490288:Gbp2b protein, mouse; D008869:Microtubule-Associated Proteins; D015800:Protozoan Proteins; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; C556793:ROP18 protein, Toxoplasma gondii; D019204:GTP-Binding Proteins
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