Tumor Necrosis Factor (Cachectin) as an Essential Mediator in Murine Cerebral Malaria

Grau, Georges E.; Fajardo, Luis F.; Piguet, P F; Allet, Bernard; Lambert, Paul‐Henri; Vassalli, Pierre

doi:10.1126/science.3306918

Cited by 686 publications

(427 citation statements)

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“…Subsequent studies demonstrating that CD4-deficient mice are also resistant to ECM confirmed a role for CD4 + T cells in disease pathogenesis (3,8). The proinflammatory cytokines IFN-g and TNF-a have been shown to be required for the pathogenesis of ECM (9,10). However, the immunologic pathway that results in the production of these cytokines during ECM has not been delineated.…”

Section: Erebral Malaria (Cm) Remains a Major Cause Of Death Inmentioning

confidence: 99%

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The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Oakley

Sahu

Lotspeich-Cole

et al. 2013

The Journal of Immunology

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The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4+ T cells. However, the role of the Th1 CD4+ T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet−deficient (Tbx21−/−) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21−/− mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21−/− mice was associated with diminished numbers of IFN-γ–producing CD4+ T cells in the spleen and a lower accumulation of CD4+ and CD8+ T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3+ CD4+ T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

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Section: Erebral Malaria (Cm) Remains a Major Cause Of Death Inmentioning

confidence: 99%

“…9D). TNF-a has long been considered a critical mediator of ECM pathogenesis (9). However, a subsequent study indicates that the related cytokine lymphotoxin-a rather than TNF-a is essential to the development of ECM (45).…”

Section: Figurementioning

confidence: 99%

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Oakley

Sahu

Lotspeich-Cole

et al. 2013

The Journal of Immunology

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“…However it is noteworthy that although blood glucose levels remained around normal (8 Plasmodium berghei Some strains of mice infected with P. berghei develop neurological manifestations of disease which coincide both with the appearance of TNF in their serum [31] and with increased levels of TNF-specific mRNA in their brains [32]. Susceptible mice infected with P. berghei did not develop hypoglycaemia during the course of infection, whether they were infected with a high or low dose of parasites.…”

Section: Plasmodium Chabaudimentioning

confidence: 99%

Malaria, blood glucose, and the role of tumour necrosis factor (TNF) in mice

Elased

Taverne

Playfair

1996

Clinical and Experimental Immunology

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SUMMARYHypoglycaemia in falciparum malaria is associated with a poor prognosis and is correlated with mortality. High levels of serum TNF are also correlated with disease severity and mortality, and it has been suggested that TNF may cause the hypoglycaemia. However hypoglycaemia in mice infected with Plasmodium chabaudi or the lethal strain of P. yoelii YM is related to hyperinsulinaemia. Its development was not prevented by treatments which diminished TNF activity or production without affecting levels of plasma insulin. Conversely, it was inhibited by diazoxide, which inhibited insulin secretion but did not affect TNF production. Furthermore, in mice exhibiting neurological symptoms during infection with P. berghei, blood glucose concentrations were significantly raised when TNF levels were high, and TNF levels in the spleen were highest of all in non-lethal P. yoelii infections in which hypoglycaemia does not occur. Administration of human rTNF to normal animals caused an increase rather than a drop in blood glucose levels. Mice transgenic for human TNF did not develop hypoglycaemia when infected with P. yoelii YM, but showed signs of insulin resistance. In line with current views on the role of TNF in obesity and the control of glucose homeostasis, we conclude that the hypoglycaemia of malaria is not caused by increased levels of TNF, which may in fact be beneficial, but is secondary to a hyperinsulinaemia that is probably stimulated directly by products of the parasite.

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“…On the other hand, lack of down-regulation of NO and TNF␣ production by stress-resistant microglia cells may contribute to the deleterious and abnormal cytokine levels associated with cerebral malaria (Grau et al, 1987;Kremsner et al, 1996;Kwiatkowski et al, 1990;Newton at al, 1998), leading to the apparently paradoxical and unexpected conclusion that oxidative stress may be beneficial in some anatomical districts. This iterates the views cautioning against labeling biological processes as exclusively favorable or exclusively noxious (Platt and Nath, 1998).…”

Section: Taramelli Et Almentioning

confidence: 99%

Macrophage Preconditioning with Synthetic Malaria Pigment Reduces Cytokine Production via Heme Iron-Dependent Oxidative Stress

Taramelli

Recalcati

Basilico

et al. 2000

Laboratory Investigation

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SUMMARY:Hemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic ␤-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor ␣ (TNF␣) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation. (Lab Invest 2000, 80:1781-1788.I ntraerythrocytic stage plasmodia digest hemoglobin in the food vacuole, where the globin is degraded and heme is detoxified, principally by polymerization/crystallization into hemozoin, an insoluble, microcrystalline derivative of ferri-protoporphyrin IX (␣ hematin, AH) (Bohle et al, 1997;Francis et al, 1997;Pagola et al, 2000;Slater et al, 1991). As parasites mature, hemozoin (malaria pigment) accumulates in the food vacuole and remains in the "residual body" after schizont rupture. Pigment is found inside host's phagocytes following ingestion of whole parasites or "residual bodies." Although a clinical correlation between the presence of pigment in circulating neutrophils and monocytes and disease severity is established (Nguyen et al, 1995), the nature of the interaction between pigment and phagocytes, as well as its contribution to the pathogenesis of malaria, and particularly its severe complications, are still controversial. Indeed, both pro-inflammatory (induction of tumor necrosis factor ␣ [TNF␣], interleukin-6 [IL-6], and chemotactic cytokines) (Pichyangkul et al, 1994;Prada et al, 1995;Sherry et al, 1995) and antiinflammatory activities (inhibition of respiratory burst and adhesion molecule expression and of TNF␣ and nitric oxide [NO] production) (Prada et al, 1995;Schwarzer et al, 1992;Taramelli et al, 1995Taramelli et al, , 1998 ha...

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Tumor Necrosis Factor (Cachectin) as an Essential Mediator in Murine Cerebral Malaria

Cited by 686 publications

References 22 publications

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Malaria, blood glucose, and the role of tumour necrosis factor (TNF) in mice

Macrophage Preconditioning with Synthetic Malaria Pigment Reduces Cytokine Production via Heme Iron-Dependent Oxidative Stress

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