Toxoplasma gondii inhibits mast cell degranulation by suppressing phospholipase Cγ-mediated Ca2+ mobilization

Abstract

Toxoplasma gondii is well-known to subvert normal immune responses, however, mechanisms are incompletely understood. In particular, its capacity to alter receptor-activated Ca2+-mediated signaling processes has not been well-characterized. In initial experiments, we found evidence that T. gondii infection inhibits Ca2+ responses to fMetLeuPhe in murine macrophages. To further characterize the mechanism of inhibition of Ca2+ 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. Ca2+ 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 Ca2+ mobilization, particularly antigen-mediated Ca2+ 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.

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

“…As T. gondii infection results in cell death or impaired immune function 52 , we infer that the capacity to perform ADDS allows mast cells to defend themselves from tachyzoite infection and consequently to produce substantial amounts of inflammatory mediators. These mediators are expected to favour the recruitment and the activation of immune cells such as neutrophils and cytotoxic lymphocytes instrumental in the defence against the parasite.…”

Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms

“…Toxoplasma gondii is also reported to inhibit MC degranulation during parasitic invasion. This parasitic infection significantly suppressed tyrosine kinase signaling cascade and its calcium cytoplasmic mobilization, which are important event during MC degranulation [68]. However, exact parasite-derived factors, inactivating MC degranulation, remain to be found.…”

Roles for Ca2+ mobilization and its regulation in mast cell functions: recent progress

“…Interestingly, inhibition of IgE/FcεRI signaling is retained when tachyzoite invasion is arrested at the attachment stage by cytochalasin D treatment, suggesting that inhibition of Syk is mediated by a parasite-derived factor that is secreted during the invasion process [33]. This study provides the first direct evidence that initiation of immune subversion by T. gondii occurs concurrently with invasion.…”