Toxoplasma gondii inhibits mast cell degranulation by suppressing phospholipase Cγ-mediated Ca(2+) mobilization
Norah L Smith1, Delbert S Abi Abdallah, Barbara A Butcher
1Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University Ithaca, NY, USA.
Abstract:
Toxoplasma gondii is well-known to subvert normal immune responses, however, mechanisms are incompletely understood. In particular, its capacity to alter receptor-activated Ca(2+)-mediated signaling processes has not been well-characterized. In initial experiments, we found evidence that T. gondii infection inhibits Ca(2+) responses to fMetLeuPhe in murine macrophages. To further characterize the mechanism of inhibition of Ca(2+) mobilization by T. gondii, we used the well-studied RBL mast cell model to probe the capacity of T. gondii to modulate IgE receptor-activated signaling within the first hour of infection. Ca(2+) mobilization that occurs via IgE/FcεRI signaling leads to granule exocytosis in mast cells. We found that T. gondii inhibits antigen-stimulated degranulation in infected cells in a strain-independent manner. Under these conditions, we found that cytoplasmic Ca(2+) mobilization, particularly antigen-mediated Ca(2+) release from intracellular stores, is significantly reduced. Furthermore, stimulation-dependent activation of Syk kinase leading to tyrosine phosphorylation and activation of phospholipase Cγ is inhibited by infection. Therefore, we conclude that inhibitory effects of infection are likely due to parasite-mediated inhibition of the tyrosine kinase signaling cascade that results in reduced hydrolysis of phosphatidylinositol 4,5-bisphosphate. Interestingly, inhibition of IgE/FcεRI signaling persists when tachyzoite invasion is arrested via cytochalasin D treatment, suggesting inhibition is mediated by a parasite-derived factor secreted into the cells during the invasion process. Our study provides direct evidence that immune subversion by T. gondii is initiated concurrently with invasion.
Insights
Toxoplasma gondii infection impairs immune cell signaling by blocking calcium responses and kinase activation. This immune subversion begins during parasite invasion, affecting crucial cellular communication pathways.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Toxoplasma gondii is known to evade host immune responses, but the precise mechanisms, especially concerning calcium signaling, remain unclear.
- Altered receptor-activated calcium (Ca2+) mediated signaling is a key aspect of immune evasion by pathogens.
- Previous findings indicated T. gondii infection inhibits Ca2+ responses in macrophages.
Purpose of the Study:
- To investigate how T. gondii modulates IgE receptor-activated signaling in RBL mast cells within the first hour of infection.
- To elucidate the mechanism by which T. gondii inhibits Ca2+ mobilization and subsequent cellular responses.
- To determine if the inhibition is strain-dependent and linked to the invasion process.
Main Methods:
- Utilized the RBL mast cell model to study IgE/FcεRI signaling pathways.
- Measured Ca2+ mobilization and antigen-stimulated degranulation in infected versus uninfected cells.
- Assessed the activation of Syk kinase and phospholipase Cγ (PLCγ) phosphorylation.
- Investigated the effect of inhibiting tachyzoite invasion (cytochalasin D) on signaling inhibition.
Main Results:
- T. gondii infection significantly inhibited antigen-stimulated degranulation in mast cells in a strain-independent manner.
- Infected cells showed reduced cytoplasmic Ca2+ mobilization, particularly release from intracellular stores.
- The study observed inhibition of Syk kinase activation, tyrosine phosphorylation, and PLCγ activation.
- Signaling inhibition persisted even when parasite invasion was blocked, suggesting a secreted factor is involved.
Conclusions:
- T. gondii actively inhibits IgE/FcεRI signaling cascades in mast cells.
- The parasite likely achieves this by secreting a factor that interferes with tyrosine kinase signaling, reducing phosphatidylinositol 4,5-bisphosphate hydrolysis.
- Immune subversion by T. gondii commences during the invasion process, impacting critical host cell signaling pathways early on.
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