Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

Pinzón-Charry, Alberto; Woodberry, Tonia; Kienzle, Vivian; McPhun, Virginia; Minigo, Gabriela; Lampah, Daniel A.; Kenangalem, Enny; Engwerda, Christian; Lopez, J. Alejandro; Anstey, Nicholas M.; Good, Michael F.

doi:10.1084/jem.20121972

Cited by 98 publications

(133 citation statements)

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“…Together, these reports suggest that, at least in a first infection, P. vivax and P. falciparum exert comparable effects on mDC subsets. In clinical vivax malaria, mDC subsets and pDC decline (12,14), with one study reporting stable pDC numbers (11). However, no studies have reported mDC subset activation, and few studies have assessed total DC activation in clinical vivax malaria (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…In Plasmodium falciparum CHMI, we previously reported loss of total peripheral blood myeloid DC (mDC) and plasmacytoid DC (pDC) (9), as well as CD1c ϩ mDC dysfunction, characterized by impaired expression of major histocompatibility complex (MHC) class II and skewed proinflammatory cytokine production (10). In areas where malaria is endemic, there is no consensus as to whether P. vivax infection leads to stable pDC and mDC numbers (11), decreases pDC and mDC numbers (12,13), or differentially affects pDC and mDC numbers (14). In adults with patent or subpatent asymptomatic P. vivax infection, pDC and mDC numbers are retained (13,15).…”

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confidence: 99%

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Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

et al. 2017

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Plasmodium vivax malaria remains a major public health problem. The requirements for acquisition of protective immunity to the species are not clear. Dendritic cells (DC) are essential for immune cell priming but also perform immune regulatory functions, along with regulatory T cells (Treg). An important function of DC involves activation of the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO). Using a controlled human experimental infection study with blood-stage P. vivax, we characterized plasmacytoid DC (pDC) and myeloid DC (mDC) subset maturation, CD4 ϩ CD25 ϩ CD127 lo Treg activation, and IDO activity. Blood samples were collected from six healthy adults preinoculation, at peak parasitemia (day 14; ϳ31,400 parasites/ml), and 24 and 48 h after antimalarial treatment. CD1c ϩ and CD141 ϩ mDC and pDC numbers markedly declined at peak parasitemia, while CD16 ϩ mDC numbers appeared less affected. HLA-DR expression was selectively reduced on CD1c ϩ mDC, increased on CD16 ϩ mDC, and was unaltered on pDC. Plasma IFN-␥ increased significantly and was correlated with an increased kynurenine/tryptophan (KT) ratio, a measure of IDO activity. At peak parasitemia, Treg presented an activated CD4 ϩ CD25 ϩ CD127 lo CD45RA Ϫ phenotype and upregulated TNFR2 expression. In a mixed-effects model, the KT ratio was positively associated with an increase in activated Treg. Our data demonstrate that a primary P. vivax infection exerts immune modulatory effects by impairing HLA-DR expression on CD1c ϩ mDC while activating CD16 ϩ mDC. Induction of the kynurenine pathway and increased Treg activation, together with skewed mDC maturation, suggest P. vivax promotes an immunosuppressive environment, likely impairing the development of a protective host immune response.

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Section: Discussionmentioning

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Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

et al. 2017

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“…The total blood mDCs are reduced in experimental infections (11), and CD1c ϩ mDCs are reduced in acute malaria (12,46), but importantly in areas of malaria endemicity, there is a preservation of blood CD1c ϩ mDC in asymptomatic carriers of P. falciparum with patent parasitemia (46). Interestingly, after the 150-pRBC infections the circulating CD1c ϩ mDCs were stable.…”

Section: P Falciparum Compromised Cd86 Expression On Cd1cmentioning

confidence: 99%

“…In acute P. falciparum malaria, CD1c ϩ mDCs decline (12) and have reduced major histocompatibility complex (MHC) class II (HLA-DR) expression in both uncomplicated (13) and severe malaria (14). However, it remains to be determined whether this impairment is evident in prepatent blood-stage P. falciparum infection, the effect of different pRBC inoculating doses, and whether CD1c ϩ mDC cytokine production is impacted by Plasmodium, informing whether CD1c ϩ mDCs can contribute to protective host adaptive immune responses.…”

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“…IL-10 is a regulatory cytokine that plays a key role in host survival, pathogen control, and the prevention of hyperinflammatory responses (22). In acute malarial infection, IL-10 has been implicated in mediating DC apoptosis (12). We sought here to understand whether CD1c ϩ mDCs produce these cytokines and whether prepatent P. falciparum infection altered their production.…”

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

et al. 2016

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dDendritic cells (DCs) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DCs (CD1c ؉ mDCs) highly express HLA-DR, have a broad Toll-like receptor (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 Plasmodium falciparum infection with 150-or 1,800-parasite-infected red blood cells (pRBCs). After either dose, CD1c؉ mDCs significantly reduced HLA-DR expression in prepatent infections. Circulating CD1c ؉ mDCs did not upregulate HLA-DR after pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c؉ mDCs produced significantly more tumor necrosis factor (TNF), whereas interleukin-12 (IL-12) production was unchanged. Interestingly, only the 1,800-pRBC dose caused a reduction in the circulating CD1c؉ mDC count with evidence of apoptosis. The 1,800-pRBC dose produced no change in T cell IFN-␥ or IL-2 production at peak parasitemia or at 3 weeks posttreatment. Overall, CD1c؉ mDCs are compromised by P. falciparum exposure, with impaired HLA-DR and CD86 expression, and have an increased capacity for TNF but not IL-12 production. A first prepatent P. falciparum infection is sufficient to modulate CD1c ؉ mDC responsiveness, likely contributing to hampered effector T cell cytokine responses and assisting parasite immune evasion.

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Transcriptional profiling and immunophenotyping show sustained activation of blood monocytes in subpatent Plasmodium falciparum infection

et al. 2020

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ObjectivesMalaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood.MethodsThe transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre‐infection or at convalescence in acute malaria.ResultsIn subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine‐mediated signalling. Monocytes increased TNF and IL‐12 production upon in vitro toll‐like receptor stimulation and increased IL‐10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16− and decreased CD14−CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA‐DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children.ConclusionsMonocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.

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Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

Abstract: Acute Plasmodium infections in humans result in dendritic cell dysfunction and apoptosis caused in part by elevated levels of IL-10.

Cited by 98 publications

References 47 publications

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

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

Transcriptional profiling and immunophenotyping show sustained activation of blood monocytes in subpatent Plasmodium falciparum infection

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Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria

Abstract: Acute Plasmodium infections in humans result in dendritic cell dysfunction and apoptosis caused in part by elevated levels of IL-10.

Cited by 98 publications

References 47 publications

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

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

Transcriptional profiling and immunophenotyping show sustained activation of blood monocytes in subpatent Plasmodium falciparum infection

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Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c ⁺ Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

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