Tumor Necrosis Factor and Disease Severity in Children with Falciparum Malaria

Grau, Georges E.; Taylor, Terrie E.; Molyneux, Malcolm E.; Wirima, Jack J.; Vassalli, Pierre; Hommel, M.; Lambert, Paul‐Henri

doi:10.1056/nejm198906153202404

Cited by 781 publications

(454 citation statements)

References 36 publications

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“…Elevated levels of proinflammatory cytokines such as TNF-␣ have been associated with disease severity and a poor prognosis, suggesting that excessive secretion of TNF-␣ by monocytes/M s in response to parasite products may promote severe and cerebral malaria (29,30,34). PPAR␥ agonists have been shown to reduce LPS and PMA-induced proinflammatory cytokine secretion from monocytes (44,45).…”

Section: Ppar␥ Agonists Reduce P Falciparum-induced Tnf-␣ From Humanmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

Serghides

Kain

2001

The Journal of Immunology

100

101

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Severe and fatal malaria is associated with the failure of host defenses to control parasite replication, excessive secretion of proinflammatory cytokines such as TNF-α, and sequestration of parasitized erythrocytes (PEs) in vital organs. The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction. This concept has been challenged by unexpected evidence that individuals deficient in CD36 are more susceptible to severe and cerebral malaria. In this study, we demonstrate that CD36 is the major receptor mediating nonopsonic phagocytosis of PEs by macrophages, a clearance mechanism of potential importance in nonimmune hosts at the greatest risk of severe malaria. CD36-mediated uptake of PEs occurs via a novel pathway that does not involve thrombospondin, the vitronectin receptor, or phosphatidylserine recognition. Furthermore, we show that proliferator-activated receptor γ-retinoid X receptor agonists induce an increase in CD36-mediated phagocytosis and a decrease in parasite-induced TNF-α secretion. Specific up-regulation of monocyte/macrophage CD36 may represent a novel therapeutic strategy to prevent or treat severe malaria.

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Section: Ppar␥ Agonists Reduce P Falciparum-induced Tnf-␣ From Humanmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

Serghides

Kain

2001

The Journal of Immunology

100

101

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“…Many studies [2][3][4] indicate that elevations in immune mediators such as IL-1, IL-6, IL-8, IL-10, TNF and NO have been associated with disease severity. In particular, high concentrations of TNF have been shown to be associated with disease severity in human Plasmodium falciparum infections and several animal malarias [2]. Mast cells can be a major source of TNF [5], suggesting that they may play an important role in mediating protection from malaria and in disease progression.…”

Section: Introductionmentioning

confidence: 99%

Mast cell‐mediated immune responses through IgE antibody and Toll‐like receptor 4 by malarial peroxiredoxin

et al. 2008

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In this study, 2-Cys Plasmodium berghei ANKA (PbA) peroxiredoxin (Prx) was identified as an antigenic protein recognized by an anti-PbA IgE antibody using two-dimensional polyacrylamide gel electrophoresis and proteomic analysis. Innate immune responses to PbAPrx were examined using cells from mice deficient in Toll-like receptors (TLR) or related molecules, and it was demonstrated that responses were severely impaired in TLR4 -/-, MyD88 -/-and MD-2 -/-mice, but not in Toll/IL-1 receptor domain-containing adaptor inducing IFN-c (TRIF) -/-, TLR2 -/-or radioprotective 105 (RP105) -/-mice. An association between PbAPrx and TLR4 was observed following immunoprecipitation and immunoblotting, suggesting that PbAPrx was associated with TLR4/MD-2. Interactions between Prx and TLR4/MD-2 were also examined by flow cytometry using TLR4/MD-2-or TLR2-expressing cells. NFjB/GFP activity was observed in TLR4/MD-2-but not in TLR2-expressing cells following stimulation with Prx. However, this effect was not observed after treatment with proteinase K, suggesting that PbAPrx is a protein ligand for TLR4 and that the PbAPrx activity observed in this study is not due to contamination with LPS. These findings indicate that malarial Prx induces IgE-mediated protection through FceRI on mast cells and innate immunity through TLR4 with MyD88 and MD-2, suggesting a novel function for malarial Prx in innate and acquired immune responses in malaria.

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“…5,6 Studies have also shown that the TNF receptor-2 (TNFR2) was upregulated during cerebral malaria in both humans and mice, 7 and more recently interferon-gamma receptor-1 gene (IFNGR1) promoter polymorphisms have been reported to be associated with cerebral malaria. 8 These results suggest that cytokines, cytokine receptors and their downstream signalling pathways are important candidates in host susceptibility to severe malaria.…”

Section: Introductionmentioning

confidence: 99%

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia

et al. 2003

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The chromosome 21q22.11 cytokine receptor cluster contains four genes that encode subunits of the receptors for the cytokines interleukin-10 and interferon-alpha, -beta and -gamma that may have a role in malaria pathogenesis. A total of 15 polymorphic markers located within these genes were initially genotyped in 190 controls and 190 severe malaria cases from The Gambia. Two interferon-alpha receptor-1 (IFNAR1) gene SNPs (17470 and L168 V) showed evidence for an association with severe malaria phenotypes and were typed in a larger series of samples comprising 538 severe malaria cases, 338 mild malaria cases and 562 controls. Both the 17470-G/G and L168V-G/G genotypes were associated with protection against severe malaria, in general, and cerebral malaria, in particular (P ¼ 0.004 and 0.003, respectively). IFNAR1 diplotypes were then constructed for these two markers using the PHASE software package. The (17470-G L168V-G/17470-G L168V-G) diplotype was found to be associated with a reduced risk of cerebral malaria and the (17470-C L168V-C/17470-G L168V-G) diplotype with an increased risk of cerebral malaria (overall 3 Â 2 w 2 ¼ 12.8, d.f. ¼ 2, P ¼ 0.002 and 3 Â 2 w 2 ¼ 15.2, d.f. ¼ 2, P ¼ 0.0005, respectively). These data suggest a role for the type I interferon pathway in resistance to cerebral malaria.

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Tumor Necrosis Factor and Disease Severity in Children with Falciparum Malaria

Cited by 781 publications

References 36 publications

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

Mast cell‐mediated immune responses through IgE antibody and Toll‐like receptor 4 by malarial peroxiredoxin

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia

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