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

PLoS Pathogens

John D. MacMicking¹  Elizabeth M. Selleck²  L. David Sibley²  Sarah J. Fentress²  Wandy L. Beatty²  Herbert W. Virgin IV³  Daniel Degrandi⁴  Klaus Pfeffer⁴ 

[1] Department of Microbial Pathogenesis, Boyer Centre for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America;Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Dusseldorf, Germany

关键词: Parasitic diseases;    Toxoplasma gondii;    Vacuoles;    Macrophages;    Autophagic cell death;    Parasitophorous vacuole;    Virulence factors;    Immunofluorescence;   

DOI  :  10.1371/journal.ppat.1003320

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY