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.
Highlights
Infection with Plasmodium is the cause of malaria, a disease characterized by a high inflammatory response in the blood
It was observed that pre-incubation of Dendritic cells (DC) with infected erythrocytes inhibits the DC maturation response triggered by different Toll-like receptors (TLR) ligands, as measured both by the expression of co-stimulatory molecules and the secretion of bioactive IL-12
Plasmodium yoelii lysates, but not whole P. yoelii-infected erythrocytes, induce DC maturation in vitro During malaria infection, DC and other immune cells are frequently exposed to parasite materials derived from lysed infected erythrocytes, and to intact infected erythrocytes, in which case Plasmodium-derived TLR ligands will be inside infected erythrocytes
Summary
Infection 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. A better understanding of innate and acquired immunity to Plasmodium parasites is required for the development of the development of effective anti-malaria strategies. Dendritic cells (DC) play a major role in host responses to pathogens, influencing both innate and adaptive immunity, as it is evident by their unique capacity to activate naïve T cells and polarize CD4+ T cell responses. Activation of Toll-like receptors (TLR) induces the maturation of DC, which is required for the generation of effective innate and T cell-mediated responses [2]. DC maturation can be induced by activation of the inflammasome [4], which can be triggered by different molecules, such as alum or uric acid [5]
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