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

Elizabeth M. Selleck, Sarah J. Fentress, Wandy L. Beatty, Daniel Degrandi, Klaus Pfeffer, Herbert W. Virgin IV, John D. MacMicking, L. David Sibley

Research output: Contribution to journalArticle

99 Scopus citations

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.

Original languageEnglish
Article numbere1003320
JournalPLoS pathogens
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2013

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