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* Department of Medicine and Center for Immunity and Inflammation, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07101;
Nuffield Department of Pathology, Oxford University, Oxford, U.K.;
Department of Cell Genetics, Institute for Genetics, University of Cologne, Cologne, Germany; and
Department of Molecular Microbiology, Washington University, St. Louis MO 63110
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.
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1 This work is supported by an R21 exploratory grant from the National Institutes of Health (AI074914 to G.S.Y.) and funds from University of Medicine and Dentistry of New Jersey-New Jersey Medical School. L.D.S. was supported by National Institutes of Health Grant AI036629.
2 Address correspondence and reprint requests to Dr. George S. Yap, Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB F-649, Newark, NJ, 07101. E-mail address: yapgs{at}umdnj.edu
3 Abbreviations used in this paper: NOS2, inducible nitric oxide synthase; PEC, peritoneal exudate cell; WT, wild type; CPS, carbamoyl phosphate synthetase II; PVM, parasitophorous vacuole membrane; IRG, immunity-related GTPase.
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