RESEARCH Open Access Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation (original) (raw)
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Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation
Malaria Journal, 2010
Background: 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.
Plasmodium Strain Determines Dendritic Cell Function Essential for Survival from Malaria
PLoS Pathogens, 2007
The severity of malaria can range from asymptomatic to lethal infections involving severe anaemia and cerebral disease. However, the molecular and cellular factors responsible for these differences in disease severity are poorly understood. Identifying the factors that mediate virulence will contribute to developing antiparasitic immune responses. Since immunity is initiated by dendritic cells (DCs), we compared their phenotype and function following infection with either a nonlethal or lethal strain of the rodent parasite, Plasmodium yoelii, to identify their contribution to disease severity. DCs from nonlethal infections were fully functional and capable of secreting cytokines and stimulating T cells. In contrast, DCs from lethal infections were not functional. We then transferred DCs from mice with nonlethal infections to mice given lethal infections and showed that these DCs mediated control of parasitemia and survival. IL-12 was necessary for survival. To our knowledge, our studies have shown for the first time that during a malaria infection, DC function is essential for survival. More importantly, the functions of these DCs are determined by the strain of parasite. Our studies may explain, in part, why natural malaria infections may have different outcomes.
Infection and Immunity, 2004
Dendritic cells (DC) suffer a maturation defect following interaction with erythrocytes infected with malaria parasites and become unable to induce protective malaria liver-stage immunity. Here we show that, by contrast, maturation-arrested DC in vitro are capable of the successful induction of antigen-specific gamma interferon (IFN-␥) and interleukin 4 (IL-4) T-cell responses, antibody responses, and potent protection against lethal blood-stage malaria challenge in vivo. Similar results were found with DC pulsed with intact parasitized Plasmodium yoelii or Plasmodium chabaudi erythrocytes. Cross-strain protection was also induced. High levels of protection (80 to 100%) against lethal challenge were evident from 10 days after a single immunization and maintained up to 120 days. Interestingly, correlation studies versus blood-stage protection at different time points suggest that the immune effector mechanisms associated with protection could change over time. Antibody-independent, T-cell-and IL-12-associated protection was observed early after immunization, followed by antibody and IL-4-associated, IFN-␥-independent protection in long-term studies. These results indicate that DC, even when clearly susceptible to parasite-induced maturation defect effects in vitro, can be central to the induction of protection against blood-stage malaria in vivo.
Scientific reports, 2017
Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to...
Different Life Cycle Stages of Plasmodium falciparum Induce Contrasting Responses in Dendritic Cells
Frontiers in Immunology
Dendritic cells are key linkers of innate and adaptive immunity. Efficient dendritic cell activation is central to the acquisition of immunity and the efficacy of vaccines. Understanding how dendritic cells are affected by Plasmodium falciparum blood-stage parasites will help to understand how immunity is acquired and maintained, and how vaccine responses may be impacted by malaria infection or exposure. This study investigates the response of dendritic cells to two different life stages of the malaria parasite, parasitized red blood cells and merozoites, using a murine model. We demonstrate that the dendritic cell responses to merozoites are robust whereas dendritic cell activation, particularly CD40 and pro-inflammatory cytokine expression, is compromised in the presence of freshly isolated parasitized red blood cells. The mechanism of dendritic cell suppression by parasitized red blood cells is host red cell membrane-independent. Furthermore, we show that cryopreserved parasitized red blood cells have a substantially reduced capacity for dendritic cell activation.
Atypical activation of dendritic cells by Plasmodium falciparum
Proceedings of the National Academy of Sciences of the United States of America, 2017
Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by Plasmodium falciparum, the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1β, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with P. falciparum-infected erythrocytes activated antigen-specific naïve CD4(+) T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to P. falciparum exhibited a transcriptional program distinct ...
Parasite Immunology, 2010
Dendritic cells (DC) and macrophages phagocytose pathogens and degrade them in their phagosomes to allow for proper presentation of foreign antigens to other cells of the immune system. The Plasmodium parasite, causative agent of malaria, infects RBC that are phagocytosed by DC and macrophages during the course of infection. Under specific conditions, the functionality of these cells can be affected by phagocytosis of Plasmodium-infected RBC. We investigated whether phagosomal maturation and degradation of Plasmodium yoelii-infected RBC in phagosomes is affected in DC and macrophages. We show that recruitment of the phagolysosomal marker Lamp-1 and of MHC-II, as well as acidification of phagosomes, was achieved in a timely manner. Using P. yoelii-infected RBC labelled with a fluorescent dye or transgenic green fluorescent protein (GFP)-expressing parasites, we found a gradual, rapid decrease in the phagosome fluorescence signal, indicating that P. yoelii-infected RBC are efficiently degraded in macrophages and DC. We also observed that pre-incubation of DC with infected RBC did not affect phagosomal maturation of newly internalized P. yoeliiinfected RBC. In conclusion, after phagocytosis, Plasmodium-infected RBC are degraded by DC and macrophages, suggesting that the process of phagosomal maturation is effectively completed in malaria.
Dendritic cells and the malaria pre-erythrocytic stage
Immunologic Research, 2012
Malaria remains one of the main infectious diseases in intertropical regions. The malaria parasite has a complex life cycle in its mammalian host, switching between variable forms as it traverses through different tissues and anatomic locations, either intra-or intercellularly. During its journey, the parasite encounters and interacts with the host immune system, which functions to prevent infections and limit ensuing pathologies. One important component of the host immune system is the dendritic cells (DC) network. DC form a heterogeneous group of pathogen-sensing and antigen-presenting cells that play a crucial role in the initiation of adaptive immunity. Here, we review the known and unknown interactions between the malaria parasites and the DC system, starting from the inoculation of the parasite in the skin up to its exit from the liver, also known as the preerythrocytic stage of the infection, and discuss how deciphering these interactions may contribute to our understanding of the Plasmodium parasite biology as well as to the induction of immune protection via vaccination.
The Journal of Immunology, 2005
Individuals living in malaria-endemic areas show generally low T cell responses to malaria Ags. In this study, we show murine dendritic cell (DC) interaction with parasitized erythrocytes (pRBC) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall T cell responses in vitro and in vivo. Moreover, within the naive T cell population, pRBC-treated DC were selectively deficient in priming CD8 ؉ but not CD4 ؉ T cells. Indeed, DC that had taken up pRBC were shown for the first time to efficiently prime CD4 ؉ T cell responses to a known protective merozoite Ag, MSP4/5. In contrast, impaired priming resulted in decreases in both proliferation and cytokine production by CD8 ؉ T cells. Deficient priming was observed to both a model and a Plasmodium berghei-specific CD8 ؉ T cell epitope. The mechanisms underlying the inability of parasite-treated DC to prime CD8 ؉ T cells were explored. pRBC treatment of DC from wild-type C57BL/6, but not from IL-10 knockout animals, suppressed DC-mediated T cell priming across a Transwell, suggesting active IL-10-dependent suppression. CD8 ؉ T cells were arrested at the G 0 stage of the cell cycle after two cell divisions post-Ag stimulation. The proliferation arrest was partially reversible by the addition of IL-2 or IL-7 to responder cultures. These results suggest that in malaria-endemic areas, priming of CD8 ؉ T cell responses may be more difficult to induce via vaccination than the priming of CD4 ؉ T cells. Moreover, pathogens may selectively target the CD8 ؉ T cell arm of protective immunity for immune evasion. The Journal of Immunology, 2005, 175: 3525-3533.
Dendritic Cell Responses and Function in Malaria
Frontiers in Immunology, 2019
Malaria remains a serious threat to global health. Sustained malaria control and, eventually, eradication will only be achieved with a broadly effective malaria vaccine. Yet a fundamental lack of knowledge about how antimalarial immunity is acquired has hindered vaccine development efforts to date. Understanding how malaria-causing parasites modulate the host immune system, specifically dendritic cells (DCs), key initiators of adaptive and vaccine antigen-based immune responses, is vital for effective vaccine design. This review comprehensively summarizes how exposure to Plasmodium spp. impacts human DC function in vivo and in vitro. We have highlighted the heterogeneity of the data observed in these studies, compared and critiqued the models used to generate our current understanding of DC function in malaria, and examined the mechanisms by which Plasmodium spp. mediate these effects. This review highlights potential research directions which could lead to improved efficacy of existing vaccines, and outlines novel targets for next-generation vaccine strategies to target malaria.