Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway

Abstract

A common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-α. IFN-α production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted γδ T cell proliferation and IFN-γ production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.

Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

“…Given these findings, hemozoin, a known parasite ligand for TLR9, is a possible candidate ligand. Hemozoin is abundant in pRBCs, and it does not induce IFN-␣ production upon stimulation of DCs (31). Indeed, hemozoin-related immune suppression has been previously reported (50).…”

“…TLR7 recognizes single-stranded RNA from viruses (23), while TLR9 recognizes DNA containing unmethylated CpG motifs (24). Recently, some reports have found that malaria parasites express molecules that are recognized by TLR9 (31,32), suggesting that TLR9 is a much more likely candidate. To confirm this, we conducted studies using mice lacking TLR7 or TLR9.…”

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

“…These results provide the first evidence that malarial Prx associates directly with TLR4. Recently, glycosyl phosphatidylinositol (GPI) [9] and hemozoin derived from Plasmodium parasites [10,11] have been identified as the ligands for TLR2 and TLR9, respectively. However, regarding TLR4 ligands in malarial studies, so far, there is no reported evidence.…”

“…However, we could not observe significant differences in parasitemia between TLR4 -/-and WT (data not shown). Since recent reported evidences indicate that glycosyl phosphatidylinositol (GPI) [9] and hemozoin derived from Plasmodium parasites [10,11] participate in innate immune responses in murine malaria, these findings might suggest that other malarial molecules also will be involved in the induction of innate resistance in murine malaria. To clarify whether malarial Prx induces a complete protective immunity in malaria or not, further experiments will be needed.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Multiple innate-sensing pathways were shown to mediate type I IFN induction by the parasite. In addition to TLR7/TLR9-dependent mechanisms (160,161), type I IFNs can be induced in a STING, TBK1, IRF3/IRF7-dependent manner via AT-rich stem-loop DNA (162). P. berghei-derived RNA also can trigger IFN-b production in a melanoma differentiation-associated protein 5/MAVS-dependent manner (163).…”