Toxoplasma GRA7 effector increases turnover of immunity-related GTPases and contributes to acute virulence in the mouse

Aditi Alaganan, Sarah J. Fentress, Keliang Tang, Qiuling Wang, L. David Sibley

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

The intracellular parasite Toxoplasma gondii enjoys a wide host range and is adept at surviving in both naive and activated macrophages. Previous studies have emphasized the importance of the active serine-threonine protein kinase rhoptry protein 18(ROP18), which targets immunity-related GTPases (IRGs), in mediating macrophage survival and acute virulence of T. gondii in mice. Here, we demonstrate that ROP18 exists in a complex with the pseudokinases rhoptry proteins 8 and 2 (ROP8/2) and dense granule protein 7 (GRA7). Individual deletion mutant Δgra7 or Δrop18 was partially attenuated for virulence in mice, whereas the combined Δgra7Δrop18 mutant was avirulent, suggesting these proteins act together in the same pathway. The virulence defect of the double mutant was mirrored by increased recruitment of IRGs and clearance of the parasite in IFN-γ-activated macrophages in vitro. GRA7 was shown to recognize a conserved feature of IRGs, binding directly to the active dimer of immunity-related GTPase a6 in a GTP-dependent manner. Binding of GRA7 to immunity-related GTPase a6 led to enhanced polymerization, rapid turnover, and eventual disassembly. Collectively, these studies suggest that ROP18 and GRA7 act in a complex to target IRGs by distinct mechanisms that are synergistic.

Original languageEnglish
Pages (from-to)1126-1131
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
StatePublished - Jan 21 2014

Keywords

  • Cooperative polymerization
  • Innate immunity
  • Pathogenesis

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