Mast cell‐mediated immune responses through IgE antibody and Toll‐like receptor 4 by malarial peroxiredoxin

Abstract

In this study, 2-Cys Plasmodium berghei ANKA (PbA) peroxiredoxin (Prx) was identified as an antigenic protein recognized by an anti-PbA IgE antibody using two-dimensional polyacrylamide gel electrophoresis and proteomic analysis. Innate immune responses to PbAPrx were examined using cells from mice deficient in Toll-like receptors (TLR) or related molecules, and it was demonstrated that responses were severely impaired in TLR4 -/-, MyD88 -/-and MD-2 -/-mice, but not in Toll/IL-1 receptor domain-containing adaptor inducing IFN-c (TRIF) -/-, TLR2 -/-or radioprotective 105 (RP105) -/-mice. An association between PbAPrx and TLR4 was observed following immunoprecipitation and immunoblotting, suggesting that PbAPrx was associated with TLR4/MD-2. Interactions between Prx and TLR4/MD-2 were also examined by flow cytometry using TLR4/MD-2-or TLR2-expressing cells. NFjB/GFP activity was observed in TLR4/MD-2-but not in TLR2-expressing cells following stimulation with Prx. However, this effect was not observed after treatment with proteinase K, suggesting that PbAPrx is a protein ligand for TLR4 and that the PbAPrx activity observed in this study is not due to contamination with LPS. These findings indicate that malarial Prx induces IgE-mediated protection through FceRI on mast cells and innate immunity through TLR4 with MyD88 and MD-2, suggesting a novel function for malarial Prx in innate and acquired immune responses in malaria.

Elevated Levels of Vascular Endothelial Growth Factor (VEGF) and Soluble Vascular Endothelial Growth Factor Receptor (VEGFR)-2 in Human Malaria

“…29 It has been reported that glycosylphosphatidylinositol and hemozoin derived from malarial parasites function as a ligand for TLR2 or TLR9 on dendritic cells, [30][31][32] and recently, we have reported that malarial peroxiredoxin recognizes TLR4 on mast cells and induces cytokine production. 18 Taken together, these findings suggest that malarial parasite components activate mast cells through TLRs to secrete various kinds of inflammatory mediators.…”

“…18,19 In this study, the level of VEGF and the soluble form of its receptors, vascular endothelial growth factor receptor (sVEGFR)-1 and -2, in the plasma from uncomplicated malaria patients and healthy adults was compared to examine the potential role of these molecules in the host immune response to malarial infection. The specific activity of malarial antigens on the secretion of VEGF by human mast cell lines was also studied.…”

Mast cells promote malaria infection?

“…[7][8][9] In particular, malarial peroxiredoxin triggers tumor necrosis factor (TNF) release from MCs through a non-IgE mechanism and decreases parasitemia in mice. 10 Remarkably, MCs are the only cell type that stores preformed TNF in their secretory granules, and once released it can activate T cells. 11,12 Cerebral malaria involves trapping of infected erythrocytes in the brain microvasculature; it was therefore of interest that vascular endothelial growth factor (VEGF) was increased in patients with cerebral malaria compared with healthy adults, and it was found that malarial parasite antigens induced VEGF secretion from human MCs.…”

Divergent Roles of IRAK4-Mediated Innate Immune Responses in Two Experimental Models of Severe Malaria

“…Several pro-inflammatory Plasmodium components are recognized by TLRs in vitro . The malaria toxin glycosylphosphatidylinositol, 25 PbA peroxiredoxin, 26 and malarial DNA complexed to parasite hemozoin 27,28 have been shown to signal through TLR2, 4, and 9, respectively. However, the degree of stimulation and the contribution of each receptor to the overall host inflammatory response and outcome of infection remain controversial.…”