The murine cerebral malaria phenomenon

White, Nicholas J.; Turner, Gareth D. H.; Medana, Isabelle M.; Dondorp, Arjen M.; Day, Nicholas P. J.

doi:10.1016/j.pt.2009.10.007

Cited by 196 publications

(185 citation statements)

References 35 publications

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“…Similar to cerebral malaria in human children, sensitive strains of mice rapidly decline into coma, with cerebral edema and hypertension (19). In contrast, adult humans with cerebral malaria exhibit a different course, with evidence indicating that inflammation and edema are less critical in older patients (13).…”

Section: Discussionmentioning

confidence: 99%

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Protective role of brain water channel AQP4 in murine cerebral malaria

Promeneur

Lunde

Amiry-Moghaddam

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tragically common among children in sub-Saharan Africa, cerebral malaria is characterized by rapid progression to coma and death. In this study, we used a model of cerebral malaria appearing in C57BL/6 WT mice after infection with the rodent malaria parasite Plasmodium berghei ANKA. Expression and cellular localization of the brain water channel aquaporin-4 (AQP4) was investigated during the neurological syndrome. Semiquantitative real-time PCR comparing uninfected and infected mice showed a reduction of brain AQP4 transcript in cerebral malaria, and immunoblots revealed reduction of brain AQP4 protein. Reduction of brain AQP4 protein was confirmed in cerebral malaria by quantitative immunogold EM; however, polarized distribution of AQP4 at the perivascular and subpial astrocyte membranes was not altered. To further examine the role of AQP4 in cerebral malaria, WT mice and littermates genetically deficient in AQP4 were infected with P. berghei. Upon development of cerebral malaria, WT and AQP4-null mice exhibited similar increases in width of perivascular astroglial endfeet in brain. Nevertheless, the AQP4-null mice exhibited more severe signs of cerebral malaria with greater brain edema, although disruption of the blood-brain barrier was similar in both groups. In longitudinal studies, cerebral malaria appeared nearly 1 d earlier in the AQP4-null mice, and reduced survival was noted when chloroquine rescue was attempted. We conclude that the water channel AQP4 confers partial protection against cerebral malaria. C erebral malaria is a dangerous complication of infection with Plasmodium falciparum, especially in children of sub-Saharan Africa, with a mortality rate of 20% (1). If untreated, cerebral malaria often causes coma and death within 24 h (2). Survivors of cerebral malaria often suffer neurological sequelae such as ataxia, hemiplegia, epilepsy, and blindness. The exact pathogenesis of cerebral malaria remains unclear. It is thought that massive sequestration of erythrocytes containing mature stages of P. falciparum within the brain microvasculature (3), as well as an excessive response of the host immune system against the malaria parasite, contribute to the disease (4).Brain edema and intracranial hypertension are common in cerebral malaria. Elevated cerebrospinal fluid pressure has been reported in more than 80% of African children with cerebral malaria (5, 6). Computed tomography of Kenyan children with cerebral malaria revealed that more than 40% had brain edema (7). More recently, increased brain volume in Malawian children with cerebral malaria based on MRI was reported (8). Severe intracranial hypertension in children with cerebral malaria is often fatal (7, 9). Autopsies of African children who died from cerebral malaria revealed brain edema (10, 11).A murine model of cerebral malaria has been established in a susceptible strain of mice (C57BL/6) infected with the rodent malaria parasite P. berghei ANKA (12). Although relevance to human cerebral malaria in adults has been questioned (13), this mo...

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Section: Discussionmentioning

confidence: 99%

“…Although relevance to human cerebral malaria in adults has been questioned (13), this model is still considered critical to study underlying mechanisms of cerebral malaria in children (14)(15)(16). In this mouse model, monocytes are sequestered in the brain microvasculature, whereas parasitized red blood cells are seen in the human disease.…”

mentioning

confidence: 99%

Protective role of brain water channel AQP4 in murine cerebral malaria

Promeneur

Lunde

Amiry-Moghaddam

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…18,69 There has, however, been significant controversy regarding the quality and relevance of these various models. The concern has focused primarily on murine models of malaria as not being representative of the human disease, 22,51,59,108,118 leading to renewed interest in malaria models in NHPs.…”

Section: Primate Malariasmentioning

confidence: 99%

A Review of Plasmodium coatneyi–Macaque Models of Severe Malaria

et al. 2015

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Malaria remains one of the most significant public health concerns in the world today. Approximately half the human population is at risk for infection, with children and pregnant women being most vulnerable. More than 90% of the total human malaria burden, which numbers in excess of 200 million annually, is due to Plasmodium falciparum. Lack of an effective vaccine and a dwindling stockpile of antimalarial drugs due to increased plasmodial resistance underscore the critical need for valid animal models. Plasmodium coatneyi was described in Southeast Asia 50 years ago. This plasmodium of nonhuman primates has been used sporadically as a model for severe malaria, as it mimics many of the pathophysiologic features of human disease. This review covers the reported macroscopic, microscopic, ultrastructural, and molecular pathology of P. coatneyi infection in macaques, specifically focusing on the rhesus macaque, as well as describing the critical needs still outstanding in the validation of this crucial model of human disease.

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“…A recent report has questioned the utility of the experimental CM model, however this report has been challenged by the research community with most investigators agreeing there are a number of features shared between human (and especially pediatric CM) and murine CM (66,67). Moreover, our approach obviates this criticism by first establishing the biological relevance of the S1P pathway to human disease by studying informative patient populations before moving to animal models to examine mechanism and causality.…”

Section: Genetic Approaches Using Hs1plmentioning

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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The murine cerebral malaria phenomenon

Cited by 196 publications

References 35 publications

Protective role of brain water channel AQP4 in murine cerebral malaria

Protective role of brain water channel AQP4 in murine cerebral malaria

A Review of Plasmodium coatneyi–Macaque Models of Severe Malaria

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

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