Guanylate-binding Protein 1 (Gbp1) Contributes to Cell-autonomous Immunity against Toxoplasma gondii

IFN-gamma 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-gamma-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 Delta rop18 or Delta rop5 parasites was associated with clearance in IFN-gamma-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Delta rop18 mutants in IFN-gamma-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-gamma-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense.