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

PLoS Pathog. 2013 Apr;9(4):e1003320. doi: 10.1371/journal.ppat.1003320. Epub 2013 Apr 25.

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

Selleck EM, Fentress SJ, Beatty WL, Degrandi D, Pfeffer K, Virgin HW 4th, Macmicking JD, Sibley LD.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

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.

PMID: 23633952 [PubMed - in process]