Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein

Emily E. Rosowski, Diana Lu, Lindsay Julien, Lauren Rodda, Rogier A. Gaiser, Kirk D C Jensen, Jeroen Saeij

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

NF-κB is an integral component of the immune response to Toxoplasma gondii. Although evidence exists that T. gondii can directly modulate the NF-κB pathway, the parasite-derived effectors involved are unknown. We determined that type II strains of T. gondii activate more NF-κB than type I or type III strains, and using forward genetics we found that this difference is a result of the polymorphic protein GRA15, a novel dense granule protein which T. gondii secretes into the host cell upon invasion. A GRA15-deficient type II strain has a severe defect in both NF-κB nuclear translocation and NF-κB - mediated transcription. Furthermore, human cells expressing type II GRA15 also activate NF-κB, demonstrating that GRA15 alone is sufficient for NF-κB activation. Along with the rhoptry protein ROP16, GRA15 is responsible for a large part of the strain differences in the induction of IL-12 secretion by infected mouse macrophages. In vivo bioluminescent imaging showed that a GRA15-deficient type II strain grows faster compared with wild-type, most likely through its reduced induction of IFN-γ. These results show for the first time that a dense granule protein can modulate host signaling pathways, and dense granule proteins can therefore join rhoptry proteins in T. gondii's host cell-modifying arsenal.

Original languageEnglish (US)
Pages (from-to)195-212
Number of pages18
JournalJournal of Experimental Medicine
Volume208
Issue number1
DOIs
StatePublished - Jan 17 2011
Externally publishedYes

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Toxoplasma
Proteins
Interleukin-12
Parasites
Macrophages

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. / Rosowski, Emily E.; Lu, Diana; Julien, Lindsay; Rodda, Lauren; Gaiser, Rogier A.; Jensen, Kirk D C; Saeij, Jeroen.

In: Journal of Experimental Medicine, Vol. 208, No. 1, 17.01.2011, p. 195-212.

Research output: Contribution to journalArticle

Rosowski, Emily E. ; Lu, Diana ; Julien, Lindsay ; Rodda, Lauren ; Gaiser, Rogier A. ; Jensen, Kirk D C ; Saeij, Jeroen. / Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 1. pp. 195-212.
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