title: Virulent Toxoplasma gondii evade immunity-related GTPase-mediated parasite vacuole disruption within primed macrophages.
abstract: Cytokine-activated macrophages restrain the replication of intracellular parasites and disrupt the integrity of vacuolar pathogens. In this study, we show that inducible nitric oxide synthase and the immunity-related GTPase (IRG) family member Irgm3, respectively, are required for the ability of in vivo primed macrophages to restrain the growth of Toxoplasma gondii and to destroy the parasite's intracellular niche. Remarkably, virulent Type I strains of T. gondii evade IRG-dependent vacuolar disruption, while remaining susceptible to iNOS-dependent restriction. The ability of virulent T. gondii to escape killing by macrophages is controlled at the level of the individual vacuole and is associated with differential permissiveness for association of the IRG proteins Irga6 (IIGP1) and Irgb6 (TGTP) to the vacuolar membrane. Surprisingly, expression of the Type I ROP-18 virulence determinant in an avirulent strain did not confer the evasive phenotype. These results pinpoint evasion of vacuolar disruption by IRG proteins as a new determinant of pathogen virulence.
authors.affiliation: Department of Medicine and Center for Immunity and Inflammation, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07101, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhao
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wilson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Howard
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
authors.forename: George S
authors.initials: GS
authors.lastname: Yap
mesh_terms: D000818:Animals; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D014122:Toxoplasma / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D014617:Vacuoles / Q000201:enzymology* / Q000276:immunology* / Q000469:parasitology; D014774:Virulence / Q000276:immunology
chemical_list: C096000:Ifi1 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C101131:Igtp protein, mouse