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 (original) (raw)
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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 ...
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.
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.
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.
Infection and immunity, 2016
Dendritic cells (DC) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DC (CD1c(+) mDC) highly express HLA-DR, have a broad TLR repertoire and secrete immune modulatory cytokines. To better understand immune responses to malaria, CD1c(+) mDC maturation and cytokine production were examined in healthy volunteers before and after experimental intravenous P. falciparum infection with 150 or 1,800 parasite-infected red blood cells (pRBC). Following either dose, CD1c(+) mDC significantly reduced HLA-DR expression in pre-patent infection. Circulating CD1c(+) mDC did not upregulate HLA-DR following pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c(+) mDC produced significantly more TNF while IL-12 production was unchanged. Interestingly, only the 1,800 pRBC dose caused a reduction in circulating CD1c(+) mDC count with evidence of apoptosis. The 1,800 pRBC dose produc...
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...
RESEARCH Open Access Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation
2013
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. Methods: Using Plasmodium yoelii, a rodent malaria model, the effect of Plasmodium-infected erythrocytes on DC maturation and TLR responses have been analysed. Results: It 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 ...
Plasmodium falciparum activates CD16+ dendritic cells to produce TNF and IL-10 in subpatent malaria
The Journal of infectious diseases, 2018
The malaria causing parasite Plasmodium subverts host immune responses by several strategies including the modulation of dendritic cells (DCs). Here, we show P. falciparum skewed CD16+ DC cytokine responses towards IL-10 production in vitro, distinct to the cytokine profile induced by toll-like receptor ligation. To determine CD16+ DC responsiveness in vivo, we assessed their function following induced P. falciparum infection in malaria-naive volunteers. CD16+ DCs underwent distinctive activation, with increased expression of maturation markers HLA-DR and CD86, enhanced TNF production and co-production of TNF/IL-10. In vitro re-stimulation with P. falciparum further increased IL-10 production. In contrast, during naturally acquired malaria episode CD16+ DCs showed diminished maturation, suggesting increased parasite burden and previous exposure influence DC subset function. These findings identify CD16+ DCs as the only DC subset activated during primary blood-stage human Plasmodium ...
European Journal of Immunology, 2008
Immunity induced by Plasmodium vivax infections leads to memory T cell recruitment and activation during subsequent infections. Here, we investigated the role of regulator T cells (Treg) in coordination with the host immune response during P. vivax infection. Our results showed a significant increase in the percentage of FOXP3 + Treg, IL-10 secreting Type I Treg (Tr1) and IL-10 levels in patients with acute P. vivax infection as compared to those found in either naïve or immune controls. The concurrent increase in the Treg population could also be reproduced in vitro using PBMC from naïve controls stimulated with crude antigens extracted from P. vivax-infected red blood cells. Acute P. vivax infections were associated with a significant decrease in the numbers of DC, indicating a general immunosuppression during P.vivax infections. However, unlike P. falciparum infections, we found that the ratio between myeloid DC (MDC) and plamacytoid (PDC) was significantly lower in acute P. vivax patients than that of naïve and immune controls. Moreover, the reduction of PDC may be partly responsible for the poor antibody responses during P. vivax infections. Taken together, these results suggest that P. vivax parasites interact with DC, which alters MDC/PDC ratio that potentially leads to Treg activation and IL-10 release.
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.