Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation

Abstract

BackgroundInfection with Plasmodium is the cause of malaria, a disease characterized by a high inflammatory response in the blood. Dendritic cells (DC) participate in both adaptive and innate immune responses, influencing the generation of inflammatory responses. DC can be activated through different receptors, which recognize specific molecules in microbes and induce the maturation of DC.MethodsUsing Plasmodium yoelii, a rodent malaria model, the effect of Plasmodium-infected erythrocytes on DC maturation and TLR responses have been analysed.ResultsIt was found that intact erythrocytes infected with P. yoelii do not induce maturation of DC unless they are lysed, suggesting that accessibility of parasite inflammatory molecules to their receptors is a key issue in the activation of DC by P. yoelii. This activation is independent of MyD88. It was also observed that pre-incubation of DC with intact P. yoelii-infected erythrocytes inhibits the maturation response of DC to other TLR stimuli. The inhibition of maturation of DC is reversible, parasite-specific and increases with the stage of parasite development, with complete inhibition induced by schizonts (mature infected erythrocytes). Plasmodium yoelii-infected erythrocytes induce a broad inhibitory effect rendering DC non-responsive to ligands for TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9.ConclusionsDespite the presence of inflammatory molecules within Plasmodium-infected erythrocytes, which are probably responsible for DC maturation induced by lysates, intact Plasmodium-infected erythrocytes induce a general inhibition of TLR responsiveness in DC. The observed effect on DC could play an important role in the pathology and suboptimal immune response observed during the disease. These results help to explain why immune functions are altered during malaria, and provide a system for the identification of a parasite-derived broad inhibitor of TLR-mediated signaling pathways.

Profoundly Reduced CD1c + Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection

“…The persistent reduction of HLA-DR despite stimulation with different TLR agonists or P. falciparum-infected pRBCs indicates that impaired HLA-DR expression was not reversible or stimulus specific. In the rodent-Plasmodium yoelii model, intact pRBCs induce a similar general inhibition of TLR responsiveness in DCs (34). At peak infection, impaired antigen presentation by splenic DCs has been shown in vivo in the rodent-Plasmodium chabaudi model (35).…”

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 + Lymphocytes

“…Conflicting data on the ability of parasites or parasite products to inhibit the maturation of dendritic cells were reported (9)(10)(11)(12) likely to be dependent on the experimental models of infection as well as on the different strains or concentrations of parasites used. Our results demonstrate that the parasitic extracts, in a range of concentrations between 0.5 and 100 g/ml of PfSE, do not interfere with the process of maturation of dendritic cells induced by LPS.…”

“…Although conflicting data were reported about the ability of parasites and/or parasite products to induce the full maturation process of dendritic cells (9)(10)(11)(12), DC have been clearly involved in TH1 differentiation of CD4 cells and also in malaria pathogenesis (13).…”

Immune Activation and Regulation in Simian Immunodeficiency Virus-Plasmodium fragile-Coinfected Rhesus Macaques

“…Monocytes exposed to hemozoin for prolonged times will downregulate Cox-2 and IL-12 and increase IL-10 production (44)(45)(46)(47), and the continued activation of monocytes will eventually result in bone marrow suppression (41,44,(47)(48)(49)(50)(51)(52). In addition, Hz can also interfere with mDC maturation (21,22,47,50,53). Although altered function of monocytes and mDC has been described extensively in severe and chronic malaria infection (15,36,41,44,51,(54)(55)(56)(57), in the current study immune dysfunction was established in coinfected animals that were clinically stable without exceedingly high parasitemia in the 3-month study period.…”

“…Malaria parasites and free hemozoin (Hz), a by-product of heme degradation by malaria parasites, can induce IL-10. At the same time, persistently elevated levels of IL-10 due to sustained levels of Hz in chronic malaria have been shown to inhibit TLR-mediated mDC function and interfere with malarial immunity (21)(22)(23). Similarly, HIV infection negatively affects TLR responses of mDC and Mo/Mph.…”