Affinage · Toxoplasma gondii

GRA15

dense granule protein GRA15 · UniProt A0A125YGQ9

Annotated
2026-09-08
59 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRA15 is a polymorphic dense granule protein secreted by Toxoplasma gondii into the host cell upon invasion, where it functions as the parasite's principal activator of the host NF-κB pathway and thereby reprograms innate immunity, inflammation, and parasite dissemination (PMID:21199955). Secreted GRA15 traffics to the host endoplasmic reticulum via its second transmembrane motif and drives NF-κB activation—IκBα phosphorylation, RelA/p65 nuclear translocation, and NF-κB-dependent transcription—by directly binding TNF-receptor-associated factors (TRAFs) through defined TRAF-binding sites, with TRAF2 required for full activity (PMID:31311877, PMID:31416833, PMID:32849602). Through this NF-κB axis GRA15 promotes classical (M1) macrophage activation in antagonism with the STAT-activating effector ROP16 (PMID:21669396), and induces a broad inflammatory program including IL-1β, IL-12, IL-18, IL-6, and CD40 (PMID:23839215, PMID:25024369, PMID:32453782). GRA15-driven, NLRP3/caspase-1/ASC-dependent IL-1β production couples the parasite to inflammasome signaling and, via IL-1β–iNOS induction, indirectly suppresses IFN-γ-induced IDO1 anti-parasite defense in hepatocytes and neurons (PMID:23839215, PMID:30301855, PMID:31119110, PMID:34006649). At the parasitophorous vacuole, GRA15 recruits TRAF2 and TRAF6 and downstream ubiquitin receptors and ubiquitin-like molecules to target the vacuole for lysosomal degradation and immunity-related GTPase attack, and promotes STING polyubiquitination and oligomerization to activate type I IFN responses (PMID:31416833, PMID:32293748). GRA15 also induces ICAM-1, CCL5/RANTES, and CCR7 in dendritic cells and brain endothelium to enhance infected-cell chemotaxis, transendothelial migration, and cerebral sequestration, and its IL-1-driven neuroinflammation increases seizure susceptibility (PMID:34154412, PMID:35990682, PMID:39207098, PMID:41528135). These activities are predominantly encoded by the type II allele, and allelic polymorphism accounts for strain-specific NF-κB output (PMID:21199955, PMID:23837824).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2011 High

    Established that a secreted parasite dense granule protein—not merely host recognition—is sufficient to activate host NF-κB, identifying GRA15 as the strain-specific driver of this response.

    Evidence Forward genetics from a type II × type III cross, GRA15 knockout, and heterologous GRA15II expression in a type I strain and human cells with NF-κB reporter assays

    PMID:21199955

    Open questions at the time
    • Molecular mechanism linking GRA15 to NF-κB not yet defined
    • Subcellular localization of GRA15 in the host cell not established
  2. 2011 High

    Placed GRA15 within a broader immunomodulatory logic by showing it drives M1 macrophage polarization in antagonism with ROP16-driven M2 polarization, jointly determining intestinal inflammation and parasite control.

    Evidence Macrophage polarization assays, genetic crosses, transgenic expression, and in vivo oral infection

    PMID:21669396

    Open questions at the time
    • Direct GRA15 effector partners not identified
    • How opposing NF-κB and STAT6 signals are integrated on shared genes unresolved
  3. 2011 Medium

    Linked GRA15 to cell-autonomous immunity by showing it contributes to strain-specific recruitment of murine GBP1 to the parasitophorous vacuole.

    Evidence Genetic crosses, transgenic parasites, and immunofluorescence for mGBP1 at the PV

    PMID:21931713

    Open questions at the time
    • Mechanism connecting GRA15/NF-κB to GBP recruitment not defined
    • Relative contribution versus ROP18/ROP16 unclear
  4. 2012 Medium

    Resolved which arms of IFN-γ signaling GRA15 controls, showing it modulates an NF-κB/IRF1-dependent gene subset while STAT1 inhibition occurs independently of GRA15.

    Evidence STAT1 reporter cell line and transcriptional profiling across clonal lineages with GRA15/ROP16 allele comparisons

    PMID:23240025

    Open questions at the time
    • The GRA15-independent STAT1 inhibitor not identified
    • Direct IRF1 engagement not mechanistically tested
  5. 2013 High

    Identified GRA15 as the parasite factor driving inflammasome-associated IL-1β, acting upstream of caspase-1/ASC via NF-κB-dependent transcription in human monocytes.

    Evidence Reciprocal GRA15 knockout and gain-of-function expression with caspase-1/ASC knockdown and IL-1β measurement

    PMID:23839215

    Open questions at the time
    • Which inflammasome sensor is engaged not defined here
    • Direct GRA15 interactors upstream of NF-κB not identified
  6. 2013 Medium

    Demonstrated GRA15 polymorphism explains differential NF-κB output even within type I strains, and that RH additionally recruits phospho-IκBα to the PV membrane partly via GRA2.

    Evidence Whole-genome SNP identification, host transcriptional profiling, NF-κB assays, and p-IκBα immunofluorescence

    PMID:23837824

    Open questions at the time
    • Specific GRA15 residues responsible for RH/GT1 divergence not mapped
    • Relationship between PV-localized p-IκBα and cytoplasmic GRA15 function unclear
  7. 2013 High

    Showed GRA15 and ROP16 cooperate genetically to promote host resistance to oral infection, refining the two effectors from purely antagonistic to context-dependent partners.

    Evidence Transgenic type II + ROP16I parasites on defined GRA15 backgrounds, oral infection, STAT-deficient mice, and macrophage killing assays

    PMID:23545295

    Open questions at the time
    • Molecular basis of GRA15/ROP16 cooperativity not defined
    • Effector-specific gene targets governing resistance not enumerated
  8. 2014 High

    Extended the GRA15 NF-κB program to costimulatory signaling by mapping NF-κB-dependent CD40 induction to GRA15, amplifying IL-12 responses.

    Evidence Forward genetics, heterologous GRA15II expression in THP-1, NF-κB inhibitor epistasis, and CD40/IL-12 readouts

    PMID:25024369

    Open questions at the time
    • Whether CD40 induction is direct or via secondary cytokines untested
    • In vivo relevance of CD40 amplification not addressed
  9. 2014 Medium

    Demonstrated evolutionary conservation of GRA15's NF-κB-activating function in the sister species Hammondia hammondi.

    Evidence Heterologous expression of HhGRA15 in T. gondii with NF-κB reporter assays

    PMID:25280815

    Open questions at the time
    • Conservation of downstream partners in H. hammondi not tested
    • Native H. hammondi host response not examined
  10. 2017 Low

    First attempt to identify direct host binding partners of GRA15, nominating mouse Luzp1 and AW209491.

    Evidence Yeast two-hybrid screen using GRA15II as bait against a mouse cDNA library

    PMID:28049510

    Open questions at the time
    • No co-IP or reciprocal validation of the interactions
    • No functional link between these partners and NF-κB established
  11. 2018 High

    Connected GRA15-driven IL-1β to suppression of host defense by showing IL-1β plus IFN-γ upregulates iNOS, which reduces the anti-Toxoplasma effector IDO1.

    Evidence GRA15-KO parasites in monocyte-hepatocyte co-culture with NLRP3 and iNOS inhibition and IDO1 readouts

    PMID:30301855

    Open questions at the time
    • Molecular mechanism of iNOS-mediated IDO1 suppression not fully defined
    • Systemic in vivo consequence of IDO1 suppression not tested here
  12. 2018 Medium

    Showed heterologously expressed GRA15II can trigger ER stress via IRE1α/JNK and TRAF2/ASK1 activation, linking GRA15 to apoptotic signaling in placental cells.

    Evidence Transfection of GRA15II into JEG-3 cells with IRE1α and JNK inhibitors and apoptosis/ER stress marker western blots

    PMID:29665822

    Open questions at the time
    • Heterologous overexpression may not reflect secreted GRA15 during infection
    • Relationship to NF-κB activation and TRAF binding not directly reconciled
  13. 2019 High

    Defined the molecular mechanism of GRA15-mediated NF-κB activation by identifying TRAF-binding sites in GRA15 and showing TRAF2 is required.

    Evidence Co-immunoprecipitation of GRA15–TRAF, TRAF-binding site deletion mutagenesis, TRAF2 knockout cells, and NF-κB reporter assays

    PMID:31311877

    Open questions at the time
    • Stoichiometry and structure of the GRA15-TRAF complex not resolved
    • Which additional TRAFs act redundantly not fully mapped
  14. 2019 High

    Localized GRA15 to the host ER via its second transmembrane motif and showed it promotes TRAF-dependent STING polyubiquitination and oligomerization to activate type I IFN.

    Evidence Subcellular fractionation, transmembrane domain mutants, STING ubiquitination/oligomerization assays, GRA15-KO parasites, and Stinggt/gt mice

    PMID:31416833

    Open questions at the time
    • Direct versus indirect action of GRA15 on the STING ubiquitination machinery unresolved
    • Identity of the ubiquitin ligase modifying STING Lys-337 not defined
  15. 2019 Medium

    Generalized the GRA15–IL-1β–iNOS–IDO1 axis to brain cells, showing GRA15 suppresses IFN-γ-induced IDO1 in human neurons.

    Evidence GRA15-KO comparison in monocyte-neuron co-cultures with IL-1β, iNOS, and IDO1 measurements

    PMID:31119110

    Open questions at the time
    • Neuron-intrinsic versus monocyte-derived signaling not fully separated
    • In vivo brain relevance not tested in this study
  16. 2020 High

    Established GRA15 as the recruiter of TRAF2/TRAF6 to the PV membrane, seeding ubiquitin receptors and ubiquitin-like conjugates that drive lysosomal and IRG-mediated vacuole destruction, with species-specific outcomes.

    Evidence GRA15-KO parasites with immunofluorescence for TRAF2/TRAF6/p62/NDP52/LC3B/GABARAP and lysosomal degradation assays in human versus murine fibroblasts

    PMID:32293748

    Open questions at the time
    • How ER-localized GRA15 delivers TRAFs to the PV membrane unclear
    • Determinants of the divergent human versus mouse outcomes not fully defined
  17. 2020 High

    Showed GRA15 is the predominant effector for IL-12/IL-18/IL-1β secretion and, with GRA24, drives IFN-γ production that controls parasite proliferation.

    Evidence GRA15/GRA24 single and double KO parasites, Tlr11-/- mice, human macrophages, and PBMC IFN-γ assays

    PMID:32453782

    Open questions at the time
    • Molecular basis of GRA15/GRA24 synergy not defined
    • Contribution of individual cytokines to IFN-γ induction not dissected
  18. 2020 High

    Confirmed GRA15 as the essential NF-κB activator among dense granule proteins, with GRA7 and GRA14 only partially contributing, and mapped its transcriptional footprint.

    Evidence Luciferase NF-κB reporter screen, GRA15/GRA7/GRA14 KO in Pru, RelA translocation and IκBα phosphorylation, and RNA-seq

    PMID:32849602

    Open questions at the time
    • How GRA7/GRA14 contribute mechanistically not defined
    • Full set of NF-κB target genes governing outcome not prioritized
  19. 2021 Medium

    Connected GRA15 to neuropathology by mapping it as the parasite gene driving brain IL-1 pathway induction and seizure susceptibility.

    Evidence QTL mapping, GRA15-KO parasites, brain gene expression, and IL-1 receptor inhibition with seizure scoring

    PMID:34154412

    Open questions at the time
    • Cell types responsible for brain IL-1β induction not fully defined
    • Direct causal chain from GRA15 to seizure circuitry unresolved
  20. 2021 Medium

    Genetically dissected the inflammasome axis, showing GRA15 is the primary driver of IL-1β release that MAG1 counteracts.

    Evidence Δmag1, Δgra15, and double-KO parasites with BMDM IL-1β ELISA and MAG1 complementation

    PMID:34006649

    Open questions at the time
    • Mechanism by which MAG1 antagonizes GRA15-driven IL-1β not defined
    • Whether antagonism occurs at transcription or inflammasome assembly unclear
  21. 2022 Medium

    Showed GRA15-driven NF-κB induces ICAM-1 on infected dendritic cells to promote adhesion and transendothelial migration, implicating GRA15 in parasite dissemination.

    Evidence GRA15-KO parasites, Icam-1 siRNA silencing in primary DCs, and transendothelial migration assays across brain endothelium

    PMID:35990682

    Open questions at the time
    • Contribution of ICAM-1 versus other NF-κB targets to migration not quantified
    • In vivo dissemination consequence tested separately
  22. 2022 Medium

    Revealed GRA15 structural diversity by characterizing a type I strain with a single-transmembrane, C-terminally extended GRA15 that still activates NF-κB, mapping the required region to residues 194–518.

    Evidence NF-κB reporter assays, IκBα phosphorylation and p65 translocation western blots, and truncation mutagenesis of T.gHB1 GRA15

    PMID:36175964

    Open questions at the time
    • Whether the single-TM variant still localizes to ER not tested
    • TRAF-binding requirement of this variant not directly examined
  23. 2024 High

    Established GRA15 as a driver of infected-cell motility for dissemination by inducing CCR7-mediated macrophage chemotaxis via NF-κB, cooperating with GRA24 and GRA28.

    Evidence GRA15/GRA24 double-KO parasites, CCR7 assays, macrophage adoptive transfer in mice, ATAC-seq, and NF-κB reporters

    PMID:39207098

    Open questions at the time
    • How NF-κB and chromatin-accessibility inputs converge on Ccr7 not fully resolved
    • Relative contribution of each effector to dissemination not partitioned
  24. 2024 Medium

    Uncovered a cell-type-specific immunosuppressive role, showing GRA15 in dendritic cells but not macrophages dampens humoral immunity and antigen-specific T cell responses.

    Evidence CD11c-Cre/GRA15 conditional knock-in mice with infection/OVA immunization, antibody titers, and flow cytometry

    PMID:39557359

    Open questions at the time
    • Mechanism of DC-specific suppression not defined
    • Reconciliation with GRA15's pro-inflammatory activity in other contexts unresolved
  25. 2026 High

    Defined a chemokine-based dissemination mechanism whereby GRA15-driven NF-κB induces CCL5/RANTES in brain endothelium and DCs to promote infected-DC hypermotility, transmigration, and cerebral sequestration reversible by CCR5 antagonism.

    Evidence GRA15-KO parasites, NF-κB reporter, CCL5 ELISA, DC transmigration, and in vivo Maraviroc treatment with intravital microscopy

    PMID:41528135

    Open questions at the time
    • Whether CCL5 acts autocrine on infected DCs or on endothelium primarily not fully separated
    • Long-term impact on cerebral parasite burden and pathology not quantified
  26. 2025 Medium

    Showed GRA15 and TgWIP promote strain-dependent sequestration of parasitized DCs in cortical capillaries, enabling post-egress invasion of cortical neurons.

    Evidence GRA15-KO and TgWIP-KO parasites delivered intracarotid into mice with in vivo brain imaging and ICAM-1/CD18 blockade

    PMID:40229286

    Open questions at the time
    • Relative contribution of GRA15 versus TgWIP to sequestration not partitioned
    • Molecular basis of strain-dependence not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ER-localized GRA15 physically delivers TRAF-dependent signaling both to the cytoplasm/nucleus and to the PV membrane, and the structural basis of the GRA15-TRAF interaction, remain unresolved.
  • No structural model of the GRA15-TRAF complex
  • Mechanism coupling ER localization to PV-membrane TRAF recruitment unknown
  • Validated direct host binding partners beyond TRAFs limited

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
AW209491 (Y2H, UNVALIDATED)LUZP1 (Y2H, UNVALIDATED)STING (VIA TRAF-DEPENDENT POLYUBIQUITINATION)TRAF2TRAF6

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 GRA15 is a novel dense granule protein secreted by Toxoplasma gondii into the host cell upon invasion, and the type II allele is sufficient to activate NF-κB nuclear translocation and NF-κB-mediated transcription in host cells. A GRA15-deficient type II strain has a severe defect in NF-κB activation, and human cells expressing type II GRA15 activate NF-κB, demonstrating GRA15 alone is sufficient for this effect. Forward genetics (type II × type III cross), GRA15 knockout, stable expression of GRA15II in type I strain and human cells, NF-κB reporter assays, in vivo bioluminescent imaging The Journal of experimental medicine High 21199955
2011 GRA15 (activating NF-κB) promotes classical (M1) macrophage activation by type II parasites, whereas ROP16 (activating STAT6) promotes alternative (M2) macrophage activation. GRA15 and ROP16 antagonistically regulate many of the same host genes, and their combined expression determines intestinal inflammation and parasite control in vivo. Macrophage polarization assays, genetic crosses, transgenic parasite expression, in vivo oral infection model Cell host & microbe High 21669396
2011 GRA15 (along with ROP16 and ROP18) is one of three parasitic factors that determine strain-specific accumulation of murine GBP1 on the parasitophorous vacuole (PV) in IFN-γ-activated cells; GRA15 contributes to GBP recruitment, linking it to the cell-autonomous immune response. Genetic crosses, transgenic parasite expression, immunofluorescence for mGBP1 localization on PV PloS one Medium 21931713
2013 GRA15 is responsible for IL-1β induction during T. gondii infection of human monocytes, acting upstream of caspase-1 and ASC (inflammasome components). A GRA15-knockout type II strain failed to induce IL-1β, and a type I strain expressing type II GRA15 gained the ability to induce IL-1β, establishing GRA15 as the parasite factor driving NF-κB-dependent IL-1β transcription. GRA15 knockout, stable transgenic expression of GRA15II in type I strain, shRNA knockdown of caspase-1 and ASC, IL-1β ELISA and transcript analysis mBio High 23839215
2013 ROP16 and GRA15 act in combination to promote host resistance to oral Toxoplasma infection; expression of STAT-activating ROP16 in type II strain promotes host resistance only when endogenous GRA15 is also present, and co-expression enhances parasite susceptibility in IFN-γ/TNF-stimulated macrophages. Transgenic parasite expression (type II + ROP16I), GRA15 genetic background, oral infection model, STAT3/6-deficient mice, macrophage killing assays Infection and immunity High 23545295
2013 GRA15 polymorphisms between RH and GT1 type I strains account for differential NF-κB activation between these strains. Furthermore, RH (but not other type I strains) recruits phosphorylated IκBα to the parasitophorous vacuole membrane in a manner partially dependent on GRA2. Whole genome sequencing (SNP identification), host transcriptional profiling, NF-κB activation assays, immunofluorescence for p-IκBα BMC genomics Medium 23837824
2014 Type II GRA15 induces expression of CD40 on infected macrophages in an NF-κB-dependent manner. Stable expression of HA-tagged GRA15II in THP-1 cells upregulated CD40 in the absence of infection. CD40 induction was mapped by forward genetics to a chromosomal region containing GRA15, and CD40L engagement of GRA15II-induced CD40 amplified the IL-12 response. Forward genetics (type II × type III cross), stable GRA15II expression in type I parasites and THP-1 cells, NF-κB inhibitor treatment, CD40 flow cytometry, IL-12 ELISA Infection and immunity High 25024369
2014 GRA15 and ROP16 from Hammondia hammondi are functionally conserved; HhGRA15 modulates host NF-κB pathway when expressed heterologously in T. gondii, confirming that GRA15's NF-κB-activating function is conserved across closely related apicomplexans. Heterologous expression of HhGRA15 in T. gondii, NF-κB reporter assays Eukaryotic cell Medium 25280815
2019 GRA15 activates the NF-κB pathway by interacting with TNF receptor-associated factors (TRAFs). Multiple TRAF-binding sites were identified in the GRA15 amino acid sequence; deletion of these sites greatly reduces NF-κB activation. TRAF2 knockout cells display impaired GRA15-mediated NF-κB activation, establishing TRAF proteins as the molecular link between GRA15 and NF-κB. Co-immunoprecipitation (GRA15–TRAF interaction), TRAF-binding site deletion mutagenesis, TRAF2 knockout cells, NF-κB reporter assays mBio High 31311877
2019 GRA15 is secreted into the host cell cytoplasm and localizes to the endoplasmic reticulum via its second transmembrane motif. GRA15 promotes STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF-dependent manner, thereby activating STING and innate immune signaling (type I IFNs). GRA15-deficient T. gondii failed to activate STING-dependent responses and was more virulent in wild-type but not Stinggt/gt mice. GRA15 subcellular fractionation/localization (ER), transmembrane domain mutants, STING polyubiquitination assay, STING oligomerization assay, GRA15-KO parasites, Stinggt/gt mice infection The Journal of biological chemistry High 31416833
2018 GRA15-dependent NF-κB activation induces NLRP3 inflammasome-dependent IL-1β production from infected monocytes; IL-1β in turn combines with IFN-γ to strongly stimulate iNOS in hepatocytes, which reduces IDO1 expression, a key IFN-γ-inducible anti-Toxoplasma effector. Thus GRA15 indirectly suppresses IFN-γ-induced IDO1-mediated cell-autonomous immunity in humans by upregulating iNOS. GRA15-KO parasites, monocyte-hepatocyte co-culture, iNOS inhibition, NLRP3 inflammasome inhibition, IDO1 expression analysis mBio High 30301855
2020 GRA15 mediates recruitment of ubiquitin ligases TRAF2 and TRAF6 to the parasitophorous vacuole membrane in human primary fibroblasts, which enhances recruitment of ubiquitin receptors (p62/NDP52) and ubiquitin-like molecules (LC3B, GABARAP), ultimately leading to lysosomal degradation of the vacuole. In murine fibroblasts, GRA15-mediated TRAF6 recruitment leads to recruitment of immunity-related GTPases and vacuole destruction. GRA15-KO parasites, immunofluorescence for TRAF2/TRAF6/p62/NDP52/LC3B/GABARAP at PV, lysosomal degradation assays, murine vs. human fibroblast comparison The EMBO journal High 32293748
2020 GRA15 and GRA24 synergistically shape innate immune responses in Tlr11-/- mice and human macrophages; GRA15 is the predominant effector for IL-12, IL-18, and IL-1β secretion in these contexts. GRA15/GRA24-mediated cytokine induction activates IFN-γ secretion by PBMCs, which controls Toxoplasma proliferation. GRA15 and GRA24 single/double KO parasites, Tlr11-/- mice infection, human macrophage infection, cytokine ELISAs, PBMC IFN-γ assay PLoS pathogens High 32453782
2020 GRA15, GRA7, and GRA14 are all involved in NF-κB activation in type II T. gondii; GRA15 is essential for NF-κB activation (nuclear translocation of RelA, phosphorylation of IκBα), while GRA7 and GRA14 only partially contribute. Deletion of GRA15 in Pru strain reduces IL-6 and shows predominantly downregulated NF-κB-mediated gene expression. Luciferase NF-κB reporter screen, GRA15/GRA7/GRA14 KO in Pru strain, immunofluorescence for RelA nuclear translocation, IκBα phosphorylation western blot, RNA-seq Frontiers in immunology High 32849602
2017 Yeast two-hybrid screening identified mouse Luzp1 and AW209491 as host binding proteins that interact with GRA15II. Yeast two-hybrid screen with mouse cDNA library using GRA15II as bait, western blot validation of bait expression Parasites & vectors Low 28049510
2012 GRA15 and ROP16 differentially modulate specific aspects of IFN-γ signaling: GRA15 activates NF-κB/IRF1 to modulate expression of a subset of IFN-γ-responsive genes, while ROP16 activates STAT3/6 to modulate a different subset. However, all three clonal lineages equally inhibit STAT1 transcriptional activity, indicating STAT1 inhibition is independent of GRA15 or ROP16. Stable STAT1-specific reporter cell line, transcriptional profiling, GRA15/ROP16 allele comparisons across clonal types PloS one Medium 23240025
2019 GRA15-dependent suppression of IFN-γ-induced IDO1 anti-parasite response operates in human neuronal cell lines and primary human neurons, in addition to hepatocytes and monocytes; the mechanism involves GRA15-induced IL-1β production leading to iNOS-dependent IDO1 suppression in brain cells. Type II T. gondii-infected THP-1 monocytes co-cultured with neuronal cell lines/primary neurons, GRA15-KO comparison, IDO1 expression assays, IL-1β and iNOS measurements Frontiers in cellular and infection microbiology Medium 31119110
2021 GRA15 is important for increased expression of IL-1β and other IL-1 pathway host genes in the brains of toxoplasmic encephalitic mice; QTL mapping identified GRA15 as the Toxoplasma gene in a locus correlating with seizure onset. Inhibiting IL-1 receptor signaling reduced seizure severity. QTL mapping, GRA15-KO parasites, mouse brain gene expression analysis, IL-1 receptor inhibitor treatment, seizure scoring mBio Medium 34154412
2021 GRA15 is required for inflammasome-induced IL-1β release during T. gondii infection; knocking out GRA15 in Δmag1 parasites completely inhibited IL-1β release, indicating GRA15 is the primary driver of IL-1β induction (which MAG1 counteracts). This confirms GRA15's role in inflammasome activation during infection. Δmag1, Δgra15, and Δmag1/Δgra15 double-KO parasites, BMDM infection, IL-1β ELISA, heterologous MAG1 complementation mBio Medium 34006649
2022 GRA15 induces ICAM-1 expression on infected dendritic cells via NF-κB signaling, which promotes enhanced cell adhesion and trans-endothelial migration (TEM). GRA15 deletion or Icam-1 gene silencing reduced TEM, while TgWIP (separately) also facilitates TEM through regulation of host actin dynamics. GRA15-KO parasites, siRNA silencing of Icam-1 in primary DCs, TEM assay across polarized brain endothelial monolayers, immunofluorescence for ICAM-1 Frontiers in immunology Medium 35990682
2024 GRA15 promotes CCR7-mediated macrophage chemotaxis by acting on the NF-κB signaling pathway. GRA15 and GRA24 (acting on NF-κB and p38 MAPK, respectively) together with GRA28-boosted chromatin accessibility at the Ccr7 gene locus drive parasite dissemination in vivo. In vivo, macrophages infected with a GRA15/GRA24 double mutant had reduced migration to secondary organs compared to WT-infected macrophages. GRA15/GRA24 double-KO parasites, CCR7 expression assays, adoptive transfer of macrophages in mice, chromatin accessibility assay (ATAC-seq), NF-κB reporter assays mBio High 39207098
2022 A newly isolated type 1 strain (T.gHB1/ToxoDB#10) carries a structurally distinct GRA15 with only one transmembrane region and an extended C-terminal region. This GRA15 activates NF-κB through IκBα phosphorylation and p65 nuclear translocation; deletion mapping showed that residues 194–518 of T.gHB1 GRA15 are required for NF-κB activation. NF-κB reporter assays, western blot for IκBα phosphorylation and p65 nuclear translocation, truncation/deletion mutagenesis of GRA15 Parasites & vectors Medium 36175964
2018 GRA15II expressed in choriocarcinoma JEG-3 cells induces endoplasmic reticulum stress (ERS) via IRE1α/JNK pathway and subsequently causes apoptosis; inhibition of IRE1α or JNK reduced GRA15II-induced apoptosis and decreased TRAF2 and ASK1 activation. Transfection of pEGFP-GRA15II into JEG-3 cells, IRE1α inhibitor (4μ8C) and JNK inhibitor (SP6000125), western blot for apoptosis/ERS markers, flow cytometry Parasites & vectors Medium 29665822
2024 GRA15 expression in dendritic cells (but not macrophages) suppresses T cell-mediated humoral immunity; conditional knock-in mice expressing GRA15 specifically in CD11c+ dendritic cells (CD11c-Cre/GRA15cKI) produced lower anti-T. gondii and anti-OVA antibody titers and had reduced numbers of antigen-specific T cells. Conditional knock-in mice (CD11c-Cre/GRA15cKI and macrophage-specific), infection and OVA immunization, antibody titer measurements, flow cytometry for plasma cells and T cells Parasitology international Medium 39557359
2026 GRA15 drives transcriptional and secretory upregulation of CCL5/RANTES in primary brain endothelial cells and dendritic cells through NF-κB signaling. CCL5 induces hypermotility and chemotaxis of infected DCs and enhances their transmigration across endothelial monolayers. In vivo, GRA15-driven CCL5 increases sequestration of infected DCs in brain microvasculature and cerebral parasite loads; CCR5 antagonist (Maraviroc) reversed sequestration. GRA15-KO parasites, NF-κB reporter assay, CCL5 ELISA, DC transmigration assay, in vivo mouse infection with Maraviroc treatment, intravital microscopy of cerebral microvasculature mBio High 41528135
2025 GRA15 and TgWIP effectors increase the sequestration of parasitized dendritic cells in cortical capillaries and cerebral parasite loads in a strain-dependent manner following intracarotid delivery; post-replicative egress from sequestered DCs enables rapid parasite localization in cortical neurons. GRA15-KO and TgWIP-KO parasites, intracarotid arterial delivery into mice, in vivo brain imaging, ICAM-1/CD18 blocking antibody treatment Nature communications Medium 40229286

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Strain-specific activation of the NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. The Journal of experimental medicine 344 21199955
2011 Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell host & microbe 186 21669396
2011 Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factors that control it. PloS one 109 21931713
2013 Human innate immunity to Toxoplasma gondii is mediated by host caspase-1 and ASC and parasite GRA15. mBio 102 23839215
2017 Identification of host proteins interacting with Toxoplasma gondii GRA15 (TgGRA15) by yeast two-hybrid system. Parasites & vectors 92 28049510
2013 Toxoplasma gondii rhoptry 16 kinase promotes host resistance to oral infection and intestinal inflammation only in the context of the dense granule protein GRA15. Infection and immunity 78 23545295
2013 Genotyping Toxoplasma gondii from wildlife in Pennsylvania and identification of natural recombinants virulent to mice. Veterinary parasitology 55 24332401
2019 Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors. mBio 50 31311877
2016 Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity. PLoS genetics 47 27447180
2012 Toxoplasma gondii clonal strains all inhibit STAT1 transcriptional activity but polymorphic effectors differentially modulate IFNγ induced gene expression and STAT1 phosphorylation. PloS one 47 23240025
2019 The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING. The Journal of biological chemistry 45 31416833
2020 Toxoplasma  GRA15 and GRA24 are important activators of the host innate immune response in the absence of TLR11. PLoS pathogens 42 32453782
2020 Toxoplasma GRA15 limits parasite growth in IFNγ-activated fibroblasts through TRAF ubiquitin ligases. The EMBO journal 42 32293748
2015 DNA vaccination with genes encoding Toxoplasma gondii antigens ROP5 and GRA15 induces protective immunity against toxoplasmosis in Kunming mice. Expert review of vaccines 42 25749394
2013 Genetic basis for phenotypic differences between different Toxoplasma gondii type I strains. BMC genomics 41 23837824
2020 Toxoplasma gondii Dense Granule Proteins 7, 14, and 15 Are Involved in Modification and Control of the Immune Response Mediated via NF-κB Pathway. Frontiers in immunology 37 32849602
2018 Inducible Nitric Oxide Synthase Is a Key Host Factor for Toxoplasma GRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response. mBio 36 30301855
2017 Macrophages Polarized by Expression of ToxoGRA15II Inhibit Growth of Hepatic Carcinoma. Frontiers in immunology 31 28243242
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