Determinants of GBP Recruitment to Toxoplasma gondii Vacuoles and the Parasitic Factors That Control It

• Main Authors: Caradonna, Kacey (Author), Burleigh, Barbara A. (Author), Winter, Sebastian Virreira (Contributor), Niedelman, Wendy Leah (Contributor), Rosowski, Emily Elizabeth (Contributor), Julien, Lindsay (Contributor), Spooner, Eric (Contributor), Saeij, Jeroen (Contributor), Ploegh, Hidde (Contributor), Frickel, Eva-Maria (Contributor), Jensen, Kirk D. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Whitehead Institute for Biomedical Research (Contributor), Jensen, Kirk D. C. (Contributor)
• Format: Article
• Language: English
• Published: Public Library of Science, 2012-02-15T18:51:21Z.
• Subjects: Article
• Online Access: Get fulltext

IFN-γ is a major cytokine that mediates resistance against the intracellular parasite Toxoplasma gondii. The p65 guanylate-binding proteins (GBPs) are strongly induced by IFN-γ. We studied the behavior of murine GBP1 (mGBP1) upon infection with T. gondii in vitro and confirmed that IFN-γ-dependent re-localization of mGBP1 to the parasitophorous vacuole (PV) correlates with the virulence type of the parasite. We identified three parasitic factors, ROP16, ROP18, and GRA15 that determine strain-specific accumulation of mGBP1 on the PV. These highly polymorphic proteins are held responsible for a large part of the strain-specific differences in virulence. Therefore, our data suggest that virulence of T. gondii in animals may rely in part on recognition by GBPs. However, phagosomes or vacuoles containing Trypanosoma cruzi did not recruit mGBP1. Co-immunoprecipitation revealed mGBP2, mGBP4, and mGBP5 as binding partners of mGBP1. Indeed, mGBP2 and mGBP5 co-localize with mGBP1 in T. gondii-infected cells. T. gondii thus elicits a cell-autonomous immune response in mice with GBPs involved. Three parasitic virulence factors and unknown IFN-γ-dependent host factors regulate this complex process. Depending on the virulence of the strains involved, numerous GBPs are brought to the PV as part of a large, multimeric structure to combat T. gondii.
National Institutes of Health (U.S.)
Massachusetts Life Sciences Center (New Investigator Award)
National Institute of General Medical Sciences (U.S.) (Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33))
Studienstiftung des deutschen Volkes
Cancer Research Institute (New York, N.Y.)
Cleo and Paul Schimmel Foundation
Bayer Healthcare
Human Frontier Science Program (Strasbourg, France)