A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction

Heyde, Henri C. van der; Nolan, John P.; Combes, Valéry; Gramaglia, Irene; Grau, Georges E.

doi:10.1016/j.pt.2006.09.002

Cited by 354 publications

(290 citation statements)

References 43 publications

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“…Since the discovery by Marchiafava and Bignami in 1894 of malaria parasites within the brain of humans during infection, attention has focussed on understanding the pathophysiological processes that predispose towards CM, with a view to the development of preventative measures or targeted therapies for the condition. Contrasting theories on the roles of parasite sequestration within the brain and the host immune response to the parasite in the pathogenesis of CM were initially proposed (reviewed by Van der Heyde et al 2006), with current understanding suggesting that neuropathology is the result of a combination of both processes, as discussed below.…”

Section: E R E B R a L M A L A R I Amentioning

confidence: 99%

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

et al. 2009

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Cerebral malaria is a life-threatening complication of malaria infection. The pathogenesis of cerebral malaria is poorly defined and progress in understanding the condition is severely hampered by the inability to study in detail, ante-mortem, the parasitological and immunological events within the brain that lead to the onset of clinical symptoms. Experimental murine models have been used to investigate the sequence of events that lead to cerebral malaria, but there is significant debate on the merits of these models and whether their study is relevant to human disease. Here we review the current understanding of the parasitological and immunological events leading to human and experimental cerebral malaria, and explain why we believe that studies with experimental models of CM are crucial to define the pathogenesis of the condition.

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Section: E R E B R a L M A L A R I Amentioning

confidence: 99%

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

et al. 2009

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“…En revanche, les souris BALB/c sont considérées comme des souris résistantes au développement du neuropaludisme. Trois hypothèses ont été émises afin d'expliquer la neuropathogenèse chez l'homme : la théorie de la perméabilité fondée sur une rupture de la barrière hémato-encéphalique (BHE), la théorie mécanique basée essentiellement sur la cytoadhérence des globules rouges infectés à l'endothélium vasculaire, et enfin la théorie immunologique qui implique les réponses immunitaires antipalustres dans la neuropathogenèse [6]. Une façon d'aborder la complexité des processus physiopathologiques du neuropaludisme est de proposer un mécanisme unifiant ces hypothèses et qui repose sur l'idée qu'une réponse inflammatoire d'un type particulier serait responsable de la pathogenèse de cette maladie.…”

Section: Relations Entre Histamine Et Infection Par Plasmodiumunclassified

Rôle de l’histamine et des récepteurs histaminiques dans la pathogenèse du paludisme

et al. 2009

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“…Plasmodium berghei ANKA (PbA) infection is an experimental model of CM (ECM) in mice that exhibits several of the neurological manifestations observed in human CM. Studies in both humans and animals have demonstrated that dysregulated inflammatory responses to infection and their effects on vascular endothelium play a central role in disease progression and outcome (2). Sphingosine 1-phosphate (S1P) is a signaling sphingolipid that regulates several cellular processes implicated in CM pathology, including inflammation and vascular endothelial homeostasis (3).…”

Section: Introductionmentioning

confidence: 99%

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney

Hawkes

Kain

et al. 2011

Mol Med

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Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL) -/-mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4 + and CD8 + T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

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A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction

Cited by 354 publications

References 43 publications

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

Rôle de l’histamine et des récepteurs histaminiques dans la pathogenèse du paludisme

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

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