Microvascular Sequestration of Parasitized Erythrocytes in Human Falciparum Malaria: a Pathological Study

Pongponratn, Emsri; Riganti, M; Punpoowong, Benjanee; Aikawa, Masamichi

doi:10.4269/ajtmh.1991.44.168

Cited by 275 publications

(205 citation statements)

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“…Several studies have pointed out that sequestration of parasitized red blood cells (PRBCs) is at the origin of this pathology, as it results in microcirculatory obstruction, decreased oxygen delivery, tissue hypoxia, metabolic acidosis, hyperlactatemia, and organ damage. This phenomenon has been reported to be higher in the brain of patients dying from CM than in other organs in the same patient and also higher than in patients without CM (MacPherson et al, 1985;Pongponratn et al, 1991). Therefore, PRBCs sequestration is necessary to the pathogenesis, but there is also evidence that it might not be sufficient by itself in initiating or maintaining the processes leading to CM and death, as demonstrated by the presence of sequestered PRBCs in non-CM cases (MacPherson et al, 1985;Montgomery et al, 2006).…”

Section: Introductionmentioning

confidence: 93%

Metabolic Acidosis Induced by Plasmodium Falciparum Intraerythrocytic Stages Alters Blood—Brain Barrier Integrity

Zougbédé

Miller

Ravassard

et al. 2010

J Cereb Blood Flow Metab

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The pathogenesis of cerebral malaria (CM) remains largely unknown. There is growing evidence that combination of both parasite and host factors could be involved in blood-brain barrier (BBB) breakdown. However, lack of adequate in vitro model of human BBB so far hampered molecular studies. In this article, we propose the use of hCMEC/D3 cells, a well-established human cerebral microvascular endothelial cell (EC) line, to study BBB breakdown induced by Plasmodium falciparum-parasitized red blood cells and environmental conditions. We show that coculture of parasitized erythrocytes with hCMEC/D3 cells induces cell adhesion and paracellular permeability increase, which correlates with disorganization of zonula occludens protein 1 expression pattern. Permeability increase and modification of tight junction proteins distribution are cytoadhesion independent. Finally, we show that permeability of hCMEC/D3 cell monolayers is mediated through parasite induced metabolic acidosis, which in turns correlates with apoptosis of parasitized erythrocytes. This new coculture model represents a very useful tool, which will improve the knowledge of BBB breakdown and the development of adjuvant therapies, together with antiparasitic drugs.

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Section: Introductionmentioning

confidence: 93%

Metabolic Acidosis Induced by Plasmodium Falciparum Intraerythrocytic Stages Alters Blood—Brain Barrier Integrity

Zougbédé

Miller

Ravassard

et al. 2010

J Cereb Blood Flow Metab

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“…Thus sticking of parasitized erythrocytes to the venular endothelium may initiate cerebral, retinal, renal, gastrointestinal, and bone marrow pathology. 19 Electron-dense knob-like protuberances on the parasitized erythrocyte membrane make contact with the vascular endothelium resulting in a mechanical obstruction and the parasites thereby also avoid clearance in the spleen and liver. Whereas membrane bound adhesion receptors promote the binding of infected red blood cells to the microvascular endothelium, soluble forms are thought to reverse this adhesion.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Looareesuwan

Sjostrom²,

Krudsood³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-␣ (TNF-␣) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-␣ (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-␥ (IFN-␥) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1␤ levels. Antibody treatment reduced IFN-␥ concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-␣ was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination halflife of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

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“…Together, these can lead to coma, organ failure and death. Many studies, both in vitro and in vivo, have shown associations between binding ability to at least some host cell receptors (principally CD36, ICAM-1 and CR1) and the occurrence of the most severe forms of disease (MacPherson et al 1985;Carlson et al 1990;Ho et al 1991;Pongponratn et al 1991;Treutiger et al 1992;Ringwald et al 1993;Rowe et al 1995;Newbold et al 1997Newbold et al , 1999Kun et al 1998;Roberts et al 2000;Pain et al 2001), whereas a few studies have found no such relationship al-Yaman et al 1995;Angkasekwinai et al 1998;Rogerson et al 1999) or a reverse one (Rogerson et al 1999). However, there is a lot to understand about how exactly cytoadherence leads to severe pathology (Berendt et al 1994;Clark & Rockett 1994;Clark & Schofield 2000;Cooke et al 2000).…”

Section: Molecular Mechanisms For Virulence In Relation To Parasite Fmentioning

confidence: 99%

Virulence in malaria: an evolutionary viewpoint

Mackinnon

Read

2004

Phil. Trans. R. Soc. Lond. B

228

205

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Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.

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Microvascular Sequestration of Parasitized Erythrocytes in Human Falciparum Malaria: a Pathological Study

Cited by 275 publications

References 0 publications

Metabolic Acidosis Induced by Plasmodium Falciparum Intraerythrocytic Stages Alters Blood—Brain Barrier Integrity

Metabolic Acidosis Induced by Plasmodium Falciparum Intraerythrocytic Stages Alters Blood—Brain Barrier Integrity

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Virulence in malaria: an evolutionary viewpoint

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