The interaction between DC and Plasmodium berghei/chabaudi‐infected erythrocytes in mice involves direct cell‐to‐cell contact, internalization and TLR

Abstract

Early interactions between blood-stage Plasmodium parasites and cells of the innate immune system are very important in shaping the adaptive immune response to malaria, and a number of studies have suggested that DC are responsible for this phenomenon. Therefore, we examined the capacity of murine BM-derived DC to internalize parasites, be activated and produce cytokines upon in vitro interaction with murine erythrocytes infected with two different strains of rodent malaria parasites (Plasmodium berghei and Plasmodium chabaudi chabaudi). We show that the increased expression of MHC class II and co-stimulatory molecules and increased production of cytokines by DC following Plasmodium infection involves internalization of infected RBC. Such DC activation not only requires direct cell-to-cell contact and internalization of infected RBC by DC but also involves TLR4, TLR9, MyD88 and signaling via NF-jB; however, TLR involvement in survival to Plasmodium infection was found to be negligible.Key words: Cell activation . Cell surface molecules . DC . Parasitic-protozoan . Phagocytosis Supporting Information available online IntroductionMalaria remains an enormous burden for the developing world, in terms of infection, morbidity and mortality. Plasmodium falciparum is the most common cause of malaria in humans, however, the difficulties in studying the human responses to infection has led to the use of experimental models of rodent malaria. Although these models do not accurately reflect all aspects of human disease, they have many characteristics in common with the human immune response to P. falciparum. Despite the use of these models and extensive research, a vaccine is not yet available and many anti-malarial drugs are increasingly ineffective due to drug resistance. A better understanding of the mechanisms that induce protective immunity to malaria infection will help to identify the strategies for vaccine development and immunotherapy.Early interactions between blood-stage parasites and cells of the innate immune system are thought to be important in shaping the adaptive immune response to malaria. Several studies using mouse models of malaria have provided evidence for an important role of DC in inducing protective immunity to blood-stage malaria [1][2][3][4][5]. Murine DC activated in vitro and in vivo by rodent Plasmodium parasites are able to express co-stimulatory molecules and produce pro-inflammatory cytokines to stimulate type 1 immune responses that are protective against malaria infection [1,4,6]. However, the interactions between the cell and the parasite that led to this activation remain poorly understood. In the present study we describe some factors involved in the interaction of DC with mouse malaria parasites that are required for the activation of the cell by the parasite.To detect microbial infection, the immune system utilizes receptors such as TLR to recognize invariant molecular structures of related microbes. TLR activation results in rapid induction of innate defense programs and ultimately...

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

“…Activation of NF-kB and MAPK signaling pathways has been demonstrated in response to a number of Plasmodium-derived factors including GPI (23), hemozoin (22), and pRBCs (24,25). Consistently, we found that both NF-kB and MAPK signaling pathways were upregulated in pRBC-stimulated BMDMs (Fig.…”

“…A critical regulator of cytokine-mediated cellular responses, NF-kB is activated downstream of a number of proinflammatory pathways and has been shown to be activated by in vitro exposure to Plasmodium-derived products (22)(23)(24)(25). Here we show NF-kB activation by P. chabaudi both in vitro and in vivo, which, in both cases, is enhanced in the context of caspase-12 deficiency.…”

IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

“…Because the molecular pathways underlying IFN-g-induced priming involve the activation of TLRs and other IFN-inducible genes (18), we compared the expression of tlr2, tlr4, tlr9, md2, cd36, il1b, stat3, irf7, and ifnar mRNAs in splenic DCs. This population is located in the red pulp of the spleen, where it is in direct contact with iRBCs, and also in the white pulp, contributing to both parasite clearance and T cell activation (27,28). We observed a significant increase in the expression of these mRNAs in DCs from mice 60d , with the exception of ifnar mRNA, whereas there was no difference between mice 200d and the AMCs (Fig.…”

“…Considering the existence of several TLR ligands in Plasmodium, such as the GPI anchor, which is recognized by the TLR2/TLR1 complex with the contribution of TLR4 (31,32), and parasite DNA, which is recognized by TLR9 (33), the long-lasting TLR hyperresponsiveness in chronic mice maintains the capacity of macrophages, DCs, and other TLR-bearing cells to recognize iRBCs and merozoites. In fact, it has been shown that DC activation not only requires direct cell-to-cell contact and internalization of iRBCs by DCs but also involves TLR4, TLR9, MyD88, and signaling via NF-kB (27). Moreover, TLR3 and TLR9 promote bacterial uptake by murine and human macrophages through the induction of a phagocytic gene program, which also is induced by TLR4 and TLR5 (34,35).…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…Thus, the polarization of Th1/Th2 immune responses will determine malarial fatalities (Hansen, Siomos et al 2003). In a mouse model utilized by Seixas et al, DCs are activated in response to pRBCs internalization, and are important in shaping the adaptive immune response to severe malaria (Seixas, Moura Nunes et al 2009). …”