title: Strain-specific activation of the NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein.
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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Rosowski
authors.forename: Diana
authors.initials: D
authors.lastname: Lu
authors.forename: Lindsay
authors.initials: L
authors.lastname: Julien
authors.forename: Lauren
authors.initials: L
authors.lastname: Rodda
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Gaiser
authors.forename: Kirk D C
authors.initials: KD
authors.lastname: Jensen
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018503:Genome, Protozoan; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D015800:Protozoan Proteins; D051996:Transcription Factor RelA; D018664:Interleukin-12